Back to resultsStudy of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
Primary Purpose
X-Linked Hypophosphatemia
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Burosumab
Sponsored by
About this trial
This is an interventional treatment trial for X-Linked Hypophosphatemia
Eligibility Criteria
Inclusion Criteria:
- Male or female, aged ≥1 year and <5 years
Diagnosis of XLH supported by ONE or more of the following
- Confirmed phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance
- Serum fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay
Biochemical findings associated with XLH including:
- Serum phosphorus < 3.0 mg/dL (0.97 mmol/L)
- Serum creatinine within age-adjusted normal range
- Radiographic evidence of rickets
- Willing to provide access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history
- Provide 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
Exclusion Criteria:
- Unwilling to stop treatment with oral phosphate and/or pharmacologic vitamin D metabolite or analog (e.g. calcitriol, alfacalcidol) during the screening period and for the duration of the study
- Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following scale: 0 = Normal, 1 = Faint hyperechogenic rim around the medullary pyramids, 2 = More intense echogenic rim with echoes faintly filling the entire pyramid, 3 = Uniformly intense echoes throughout the pyramid, 4 = Stone formation: solitary focus of echoes at the tip of the pyramid
- Planned or recommended orthopedic surgery including staples, 8-plates or osteotomy, within the clinical trial period
- Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
- 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 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
Sites / Locations
- Yale University School of Medicine
- Indiana University School of Medicine
- Shriners Hospital for Children
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Burosumab Q2W
Arm Description
Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks.
Outcomes
Primary Outcome Measures
Change From Baseline at Week 40 in Serum Phosphorus
The Generalized Estimation Equation (GEE) model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death).
Secondary Outcome Measures
Radiographic Global Impression of Change (RGI-C) Score at Week 40
Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The Analysis of Covariance (ANCOVA) model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
RGI-C Score at Week 64
Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score
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.The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score
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, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. The GEE model includes the change from baseline in RSS as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
RGI-C Lower Limb Deformity Score at Week 40
Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
RGI-C Lower Limb Deformity Score at Week 64
Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Change From Baseline Over Time in Recumbent Length/Standing Height
Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores
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.
Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles
Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)
The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
Percent Change From Baseline Over Time in Serum ALP
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02750618
Brief Title
Study of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
Official Title
An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
May 5, 2016 (Actual)
Primary Completion Date
April 20, 2017 (Actual)
Study Completion Date
September 10, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kyowa Kirin, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary objectives of the study are to:
Establish the safety profile of KRN23 for the treatment of XLH in children between 1 and 4 years old
Determine the PD effects of KRN23 treatment on serum phosphorus and other PD markers that reflect the status of phosphate homeostasis in children between 1 and 4 years old with XLH
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
X-Linked Hypophosphatemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Burosumab Q2W
Arm Type
Experimental
Arm Description
Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks.
Intervention Type
Biological
Intervention Name(s)
Burosumab
Other Intervention Name(s)
KRN23, Crysvita®, UX023
Intervention Description
solution for subcutaneous injection
Primary Outcome Measure Information:
Title
Change From Baseline at Week 40 in Serum Phosphorus
Description
The Generalized Estimation Equation (GEE) model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
Time Frame
Baseline, Week 40
Title
Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
Description
An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death).
Time Frame
From first dose of study drug through the end of the study (Week 160). Maximum duration of exposure to study drug was 160 weeks.
Secondary Outcome Measure Information:
Title
Radiographic Global Impression of Change (RGI-C) Score at Week 40
Description
Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The Analysis of Covariance (ANCOVA) model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
Time Frame
Week 40
Title
RGI-C Score at Week 64
Description
Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Time Frame
Week 64
Title
Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score
Description
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.The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
Time Frame
Baseline, Week 40
Title
Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score
Description
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, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. The GEE model includes the change from baseline in RSS as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Time Frame
Baseline, Week 64
Title
RGI-C Lower Limb Deformity Score at Week 40
Description
Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
Time Frame
Week 40
Title
RGI-C Lower Limb Deformity Score at Week 64
Description
Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven 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). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Time Frame
Week 64
Title
Change From Baseline Over Time in Recumbent Length/Standing Height
Time Frame
Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
Title
Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores
Description
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, Weeks 12, 24, 40, 64, 88, 112, 136, 160
Title
Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles
Time Frame
Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
Title
Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)
Description
The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
Time Frame
Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160
Title
Percent Change From Baseline Over Time in Serum ALP
Time Frame
Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female, aged ≥1 year and <5 years
Diagnosis of XLH supported by ONE or more of the following
Confirmed phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance
Serum fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay
Biochemical findings associated with XLH including:
Serum phosphorus < 3.0 mg/dL (0.97 mmol/L)
Serum creatinine within age-adjusted normal range
Radiographic evidence of rickets
Willing to provide access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history
Provide 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
Exclusion Criteria:
Unwilling to stop treatment with oral phosphate and/or pharmacologic vitamin D metabolite or analog (e.g. calcitriol, alfacalcidol) during the screening period and for the duration of the study
Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following scale: 0 = Normal, 1 = Faint hyperechogenic rim around the medullary pyramids, 2 = More intense echogenic rim with echoes faintly filling the entire pyramid, 3 = Uniformly intense echoes throughout the pyramid, 4 = Stone formation: solitary focus of echoes at the tip of the pyramid
Planned or recommended orthopedic surgery including staples, 8-plates or osteotomy, within the clinical trial period
Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Ultragenyx Pharmaceutical Inc
Official's Role
Study Director
Facility Information:
Facility Name
Yale University School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
Indiana University School of Medicine
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Shriners Hospital for Children
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
32721016
Citation
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.
Results Reference
derived
PubMed Identifier
30638856
Citation
Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, Imel EA. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019 Mar;7(3):189-199. doi: 10.1016/S2213-8587(18)30338-3. Epub 2019 Jan 9.
Results Reference
derived
Learn more about this trial
Study of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
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