X-Linked HypophosphatemiaPhase 3NCT02915705
Efficacy and Safety of Burosumab Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With XLH
A Phase 3 study testing burosumab, Oral Phosphate Supplement and active vitamin D in people with X-Linked Hypophosphatemia, run by Kyowa Kirin, Inc. at 16 sites in 7 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 1 year to 12 years
- Conditions the study is for
- X-Linked Hypophosphatemia
- What is being tested?
- burosumab, Oral Phosphate Supplement and active vitamin D
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 61 participants
- Where
- 16 sitesin 7 countries
- Study dates
- 8 Sep 2016to 15 Jul 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 12 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
16 sites in 7 countries.
16 sites in 7 countries
United States5 sites
Indiana University School of Medicine
Indianapolis, Indiana, 46202
Children's Hospital Los Angeles
Los Angeles, California, 90027
Vanderbilt Children's Hospital
Nashville, Tennessee, 37232
UCSF
San Francisco, California, 94158
Shriners Hospital For Children
St Louis, Missouri, 63110
Canada3 sites
Shriners Hospital for Children - Canada
Montreal, Quebec, H4A 0A9
Children's Hospital of Eastern Ontario (CHEO) Research Institute
Ottawa, Ontario, K1H 8L1
The Hospital for Sick Children
Toronto, Ontario, M5G 1X8
Japan3 sites
Okayama Saiseikai General Hospital
Okayama, 700-0013
Japan Community Healthcare Organization Osaka Hospital
Osaka, 553-0003
Kanagawa Children's Medical Center
Yokohama, Kanagawa, 232-8555
United Kingdom2 sites
Birmingham Children's Hospital
Birmingham, B4 6NH
Royal Manchester Children's Hospital - University of Manchester
Manchester, M13 9WL
Australia1 site
The Children's Hospital at Westmead
Westmead, New South Wales, 2145
About this study
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)
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).
- Conditions
- X-Linked Hypophosphatemia
- Being tested
- burosumab, Oral Phosphate Supplement, active vitamin D
- Medical subject headings
- Familial Hypophosphatemic Rickets
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
burosumabBiological
Also called KRN23, Crysvita ®, UX023
solution for subcutaneous (SC) injection
Oral Phosphate SupplementDrug
oral tablet; oral solution; oral powder
active vitamin DDrug
tablet, oral solution
| Study group | Role | What they receive |
|---|---|---|
| Burosumab | Experimental | 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. Receives: Biological: burosumab |
| Active Control | Active comparator | 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. Receives: Biological: burosumab; Drug: Oral Phosphate Supplement; Drug: active vitamin D |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Week 40
Secondary outcomes (31)
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).
Measured: Week 40
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).
Measured: Week 64
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).
Measured: Week 64
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.
Measured: Baseline, Week 40
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.
Measured: Baseline, Week 64
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).
Measured: Week 40
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).
Measured: Week 64
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.
Measured: Baseline, Week 40
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.
Measured: Baseline, Week 64
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.
Measured: Baseline, Week 40
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.
Measured: Baseline, Week 64
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.
Measured: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112
Measured: Baseline, Weeks 66, 68, 76, 88, 100, 112
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.
Measured: Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64
Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)
Measured: 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
Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)
Measured: Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140
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.
Measured: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112
Measured: Baseline, Weeks 68, 76, 88, 100, 112
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.
Measured: Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64
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.
Measured: Baseline, Weeks 68, 76, 88, 112
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.
Measured: Baseline, Weeks 16, 24, 40, 52, 64
Change From Baseline Over Time in Serum ALP, Week 68 to 112
Measured: Baseline, Weeks 68, 76, 88, 100, 112
Percent Change From Baseline Over Time in Serum ALP, up to Week 112
Decreases indicate improvement.
Measured: Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112
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.
Measured: Baseline, Week 40
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.
Measured: Baseline, Week 64
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.
Measured: Baseline, Week 40
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.
Measured: Baseline, Week 64
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.
Measured: Baseline, Week 40
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.
Measured: Baseline, Week 64
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.
Measured: Baseline, Week 40
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.
Measured: Baseline, Week 64
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Sep 2016 (estimated)
- Study start8 Sep 2016
- Primary completion12 Feb 2018
- Study completion15 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for X-Linked HypophosphatemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 61 participants (actual)
Sponsor and investigators
- Lead sponsor
- Kyowa Kirin, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Kyowa Kirin Co., Ltd.
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Ultragenyx Pharmaceutical Inc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02915705
- Sponsor's protocol ID
- UX023-CL301
- Status last verified
- Aug 2024
- First submitted
- 23 May 2016
- Last updated
- 29 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Expanded access
- Available
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 39151033Imel 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 37084401Ward 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 35533340Padidela 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 33484279Mao 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 32721016Imel 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 at a glance
From the registry record, last updated by the sponsor on 29 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02915705
- Acronym / sponsor ID
- UX023-CL301
- Conditions
- X-Linked Hypophosphatemia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 61 participants (actual)
- Lead sponsor
- Kyowa Kirin, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Kyowa Kirin Co., Ltd.
- Study start
- 8 Sep 2016 (actual)
- Primary completion
- 12 Feb 2018 (actual)
- Study completion
- 15 Jul 2019 (actual)
- First posted
- 27 Sep 2016 (estimated)
- Results
- Posted 11 Apr 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Burosumab | Experimental | Biological: burosumabBurosumab 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. |
| Active Control | Active comparator | Biological: burosumab, Drug: Oral Phosphate Supplement, Drug: active vitamin DMultiple 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. |
Who may qualify
- Ages
- 1 year to 12 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (10 listed)
- 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
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| burosumabAlso: KRN23, Crysvita ®, UX023solution for subcutaneous (SC) injection | Biological | Active Control, Burosumab |
| Oral Phosphate Supplementoral tablet; oral solution; oral powder | Drug | Active Control |
| active vitamin Dtablet, oral solution | Drug | Active Control |
Primary outcome
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).
31 secondary outcomes
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40
Time frame: Week 40
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64
Time frame: Week 64
RGI-C Global Score at Week 64
Time frame: Week 64
Change From Baseline in RSS Total Score at Week 40
Time frame: Baseline, Week 40
Change From Baseline in RSS Total Score at Week 64
Time frame: Baseline, Week 64
RGI-C Long Leg Score at Week 40
Time frame: Week 40
RGI-C Long Leg Score at Week 64
Time frame: Week 64
Change From Baseline in Height-For-Age Z-Scores to Week 40
Time frame: Baseline, Week 40
Change From Baseline in Height-For-Age Z-Scores to Week 64
Time frame: Baseline, Week 64
Change in Growth Velocity Z Score From Baseline to Week 40
Time frame: Baseline, Week 40
Change in Growth Velocity Z Score From Baseline to Week 64
Time frame: Baseline, Week 64
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
Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112
Time frame: Baseline, Weeks 66, 68, 76, 88, 100, 112
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
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
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
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
Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112
Time frame: Baseline, Weeks 68, 76, 88, 100, 112
Change From Baseline Over Time in TmP/GFR, up to Week 64
Time frame: Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64
Change From Baseline Over Time in TmP/GFR, Week 68 to 112
Time frame: Baseline, Weeks 68, 76, 88, 112
Change From Baseline Over Time in Serum ALP, up to Week 64
Time frame: Baseline, Weeks 16, 24, 40, 52, 64
Change From Baseline Over Time in Serum ALP, Week 68 to 112
Time frame: Baseline, Weeks 68, 76, 88, 100, 112
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
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
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
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
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
Change From Baseline in the 6MWT Total Distance at Week 40
Time frame: Baseline, Week 40
Change From Baseline in the 6MWT Total Distance at Week 64
Time frame: Baseline, Week 64
Percent of Predicted Normal in the 6MWT Total Distance at Week 40
Time frame: Baseline, Week 40
Percent of Predicted Normal in the 6MWT Total Distance at Week 64
Time frame: Baseline, Week 64
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39151033Portale 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.
- Derived from this study: PubMed 37084401Imel 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.
- Derived from this study: PubMed 35533340Ward 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.
- Derived from this study: PubMed 33484279Padidela 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.
- Derived from this study: PubMed 32721016Mao 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.
- Derived from this study: PubMed 31104833Imel 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Ultragenyx Pharmaceutical Inc
16 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing burosumab, Oral Phosphate Supplement and active vitamin D in people with X-Linked Hypophosphatemia, run by Kyowa Kirin, Inc. at 16 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in United States, Canada, Japan, United Kingdom, Australia and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Radiographic Global Impression of Change (RGI-C) Global Score at Week 40 (time frame: Week 40). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02915705, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Aug 2024.