X-Linked Hypophosphatemia
Conditions
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
Interventions
BIOLOGICALBurosumab
solution for subcutaneous injection
Sponsors
Kyowa Kirin, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 4 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged ≥1 year and \<5 years 2. 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 3. Biochemical findings associated with XLH including: * Serum phosphorus \< 3.0 mg/dL (0.97 mmol/L) * Serum creatinine within age-adjusted normal range 4. Radiographic evidence of rickets 5. Willing to provide access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history 6. 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 7. 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
1. 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 2. 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 3. Planned or recommended orthopedic surgery including staples, 8-plates or osteotomy, within the clinical trial period 4. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits 5. 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 6. Presence of a concurrent disease or condition that would interfere with study participation or affect safety 7. History of recurrent infection or predisposition to infection, or of known immunodeficiency 8. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 40 in Serum Phosphorus | Baseline, Week 40 | 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 | From first dose of study drug through the end of the study (Week 160). Maximum duration of exposure to study drug was 160 weeks. | 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
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score | 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, 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 | 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, 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 | 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 | 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. |
| Radiographic Global Impression of Change (RGI-C) Score at Week 40 | 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. |
| Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 | 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 | Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 | — |
| Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160 | 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 | Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160 | — |
| Change From Baseline Over Time in Recumbent Length/Standing Height | Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 | — |
| RGI-C Score at Week 64 | 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. |
Countries
United States
Participant flow
Pre-assignment details
The study enrolled pediatric participants between 1 and 4 years old, inclusive, with clinical findings consistent with XLH including hypophosphatemia and radiographic evidence of rickets, and a confirmed PHEX mutation or variant of uncertain significance.
Participants by arm
| Arm | Count |
|---|---|
| Burosumab Q2W Burosumab SC injections Q2W for a total of 160 weeks. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Burosumab Q2W |
|---|---|
| Age, Continuous | 2.94 years STANDARD_DEVIATION 1.146 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized White | 12 Participants |
| Recumbent length/Standing height | 89.15 cm STANDARD_DEVIATION 7.597 |
| Recumbent length/Standing height (percentile) | 18.044 percentile STANDARD_DEVIATION 25.2644 |
| Recumbent length/Standing height (Z score) | -1.378 Z score STANDARD_DEVIATION 1.1947 |
| Rickets Severity Score (RSS) Total Score | 2.92 units on a scale STANDARD_DEVIATION 1.367 |
| Serum Alkaline Phosphatase (ALP) | 548.5 U/L STANDARD_DEVIATION 193.8 |
| Serum Phosphorus | 2.51 mg/dL STANDARD_DEVIATION 0.284 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 1 / 13 |
Outcome results
Primary
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.
Time frame: Baseline, Week 40
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Burosumab Q2W | Change From Baseline at Week 40 in Serum Phosphorus | 0.96 mg/dL | Standard Error 0.117 |
p-value: <0.000195% CI: [0.73, 1.19]GEE model
Primary
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).
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.
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Adverse Event Starting during Screening Period | 5 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs | 13 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Related TEAEs | 5 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious TEAEs | 1 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious Related TEAEs | 0 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Grade 3 or 4 TEAE | 2 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAE Leading to Study Discontinuation | 0 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAE Leading to Treatment Discontinuation | 0 Participants |
| Burosumab Q2W | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAE Leading to Death | 0 Participants |
Secondary
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.
Time frame: Baseline, Week 40
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score | -1.75 units on a scale | Standard Error 0.116 |
p-value: <0.000195% CI: [-1.98, -1.53]GEE model
Secondary
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.
Time frame: Baseline, Week 64
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score | -2.02 units on a scale | Standard Error 0.115 |
p-value: <0.000195% CI: [-2.25, -1.8]GEE model
Secondary
Change From Baseline Over Time in Recumbent Length/Standing Height
Time frame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 12 | 1.44 cm | Standard Deviation 2.009 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 24 | 2.52 cm | Standard Deviation 1.518 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 40 | 4.29 cm | Standard Deviation 2.451 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 64 | 7.22 cm | Standard Deviation 3.157 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 88 | 10.30 cm | Standard Deviation 3.4 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 112 | 13.25 cm | Standard Deviation 3.724 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 136 | 15.41 cm | Standard Deviation 3.699 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height | Week 160 | 18.96 cm | Standard Deviation 4.206 |
Secondary
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.
Time frame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 12 | -0.082 Z score | Standard Deviation 0.4964 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 24 | -0.208 Z score | Standard Deviation 0.454 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 40 | -0.276 Z score | Standard Deviation 0.6647 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 64 | -0.264 Z score | Standard Deviation 0.8755 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 88 | -0.212 Z score | Standard Deviation 0.9115 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 112 | -0.174 Z score | Standard Deviation 0.9273 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 136 | -0.321 Z score | Standard Deviation 0.9123 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores | Week 160 | -0.172 Z score | Standard Deviation 0.9048 |
Secondary
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
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 12 | -0.006 percentiles | Standard Deviation 11.6149 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 24 | -4.940 percentiles | Standard Deviation 13.1323 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 40 | -5.283 percentiles | Standard Deviation 20.1675 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 64 | -4.980 percentiles | Standard Deviation 23.4412 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 88 | -4.155 percentiles | Standard Deviation 23.9126 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 112 | -3.000 percentiles | Standard Deviation 24.7569 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 136 | -7.026 percentiles | Standard Deviation 24.8583 |
| Burosumab Q2W | Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles | Week 160 | -3.628 percentiles | Standard Deviation 25.5113 |
Secondary
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.
Time frame: Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160
Population: PK/PD Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 4 | -82.91 U/L | Standard Error 23.348 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 12 | -83.84 U/L | Standard Error 45.263 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 20 | -161.38 U/L | Standard Error 12.924 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 40 | -214.99 U/L | Standard Error 13.628 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 48 | -226.58 U/L | Standard Error 11.491 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 56 | -216.45 U/L | Standard Error 16.165 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 64 | -216.76 U/L | Standard Error 12.705 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 76 | -231.22 U/L | Standard Error 15.964 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 88 | -237.78 U/L | Standard Error 12.837 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 100 | -218.14 U/L | Standard Error 15.34 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 112 | -233.91 U/L | Standard Error 11.098 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 124 | -252.22 U/L | Standard Error 8.312 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 136 | -267.89 U/L | Standard Error 13.124 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 148 | -248.05 U/L | Standard Error 12.653 |
| Burosumab Q2W | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 160 | -248.47 U/L | Standard Error 10.99 |
Comparison: Week 4p-value: 0.000495% CI: [-128.68, -37.15]GEE model
Comparison: Week 12p-value: 0.06495% CI: [-172.55, 4.88]GEE model
Comparison: Week 20p-value: <0.000195% CI: [-186.7, -136.05]GEE model
Comparison: Week 40p-value: <0.000195% CI: [-241.7, -188.28]GEE model
Comparison: Week 48p-value: <0.000195% CI: [-249.11, -204.06]GEE model
Comparison: Week 56p-value: <0.000195% CI: [-248.13, -184.77]GEE model
Comparison: Week 64p-value: <0.000195% CI: [-241.66, -191.86]GEE model
Comparison: Week 76p-value: <0.000195% CI: [-262.51, -199.93]GEE
Comparison: Week 88p-value: <0.000195% CI: [-262.94, -212.62]GEE
Comparison: Week 100p-value: <0.000195% CI: [-248.21, -188.08]GEE
Comparison: Week 112p-value: <0.000195% CI: [-255.66, -212.16]GEE
Comparison: Week 124p-value: <0.000195% CI: [-268.51, -235.93]GEE
Comparison: Week 136p-value: <0.000195% CI: [-293.61, -242.16]GEE
Comparison: Week 148p-value: <0.000195% CI: [-272.85, -223.25]GEE
Comparison: Week 160p-value: <0.000195% CI: [-270.01, -226.93]GEE
Secondary
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
Population: PK/PD Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 136 | -47.01 percent change | Standard Deviation 11.752 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 4 | -12.47 percent change | Standard Deviation 16.62 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 12 | -5.00 percent change | Standard Deviation 60.124 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 20 | -24.76 percent change | Standard Deviation 18.883 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 40 | -36.25 percent change | Standard Deviation 12.787 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 48 | -37.29 percent change | Standard Deviation 13.936 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 56 | -35.80 percent change | Standard Deviation 16.568 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 64 | -35.95 percent change | Standard Deviation 14.851 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 76 | -38.36 percent change | Standard Deviation 15.621 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 88 | -39.08 percent change | Standard Deviation 12.987 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 100 | -37.42 percent change | Standard Deviation 12.466 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 112 | -39.05 percent change | Standard Deviation 13.808 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 124 | -43.11 percent change | Standard Deviation 12.493 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 148 | -43.47 percent change | Standard Deviation 11.321 |
| Burosumab Q2W | Percent Change From Baseline Over Time in Serum ALP | Week 160 | -42.35 percent change | Standard Deviation 13.574 |
Secondary
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.
Time frame: Week 40
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Burosumab Q2W | Radiographic Global Impression of Change (RGI-C) Score at Week 40 | 2.21 units on a scale | Standard Error 0.071 |
p-value: <0.000195% CI: [2.07, 2.35]GEE model
Secondary
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.
Time frame: Week 40
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Burosumab Q2W | RGI-C Lower Limb Deformity Score at Week 40 | 1.21 units on a scale | Standard Error 0.155 |
p-value: <0.000195% CI: [0.9, 1.51]GEE model
Secondary
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.
Time frame: Week 64
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Burosumab Q2W | RGI-C Lower Limb Deformity Score at Week 64 | 1.51 units on a scale | Standard Error 0.123 |
p-value: <0.000195% CI: [1.27, 1.76]GEE
Secondary
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.
Time frame: Week 64
Population: Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Burosumab Q2W | RGI-C Score at Week 64 | 2.23 units on a scale | Standard Error 0.111 |
Comparison: 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. The least squares (LS) mean, standard error (SE), 95% confidence interval (CI) and 2-sided p-value are from the GEE model.p-value: <0.000195% CI: [2.01, 2.45]GEE model