X-linked Hypophosphatemia
Conditions
Keywords
X-linked hypophosphatemia, XLH, FGF23, KRN23
Brief summary
The objectives of the study are to: * Identify a dose and dosing regimen of burosumab, based on safety and pharmacodynamic (PD) effect, in pediatric XLH participants * Establish the safety profile of burosumab for the treatment of children with XLH including ectopic mineralization risk, cardiovascular effects, and immunogenicity profile * Characterize the pharmacokinetic (PK)/PD profile of the KRN23 doses tested in the monthly (Q4) and biweekly (Q2) dose regimens in pediatric XLH patients * Determine the PD effects of burosumab treatment on markers of bone health in pediatric XLH patients * Obtain a preliminary assessment of the clinical effects of burosumab on bone health and deformity, muscle strength, and motor function * Obtain a preliminary assessment of the effects of burosumab on participant-reported outcomes, including pain, disability, and quality of life in pediatric XLH patients * Evaluate the long-term safety and efficacy of burosumab
Interventions
BIOLOGICALburosumab
solution for SC injection
Sponsors
Kyowa Kirin Co., Ltd.
Kyowa Kirin, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
Inclusion 1. Male or female, aged 5 - 12 years, inclusive, with open growth plates 2. Tanner stage of 2 or less based on breast and testicular development 3. Diagnosis of XLH supported by ONE 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 FGF23 level \> 30 pg/mL by Kainos assay 4. Biochemical findings associated with XLH including: * Serum phosphorus ≤ 2.8 mg/dL (0.904 mmol/L)\* * Serum creatinine within age-adjusted normal range\* 5. Standing height \< 50th percentile for age and gender using local normative data. 6. Radiographic evidence of active bone disease including rickets in the wrists and/or knees, AND/OR femoral/tibial bowing, OR, for expansion subjects, a Rickets Severity Score (RSS) score in the knee of at least 1.5 as determined by central read. 7. Willing to provide access to prior medical records for the collection of historical growth, biochemical and radiographic data, and disease history. 8. Provide written or verbal assent (if possible) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures. 9. Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments. 10. Females who have reached menarche must have a negative pregnancy test at Screening and undergo additional pregnancy testing during the study. If sexually active, male and female subjects must be willing to use an acceptable method of contraception for the duration of the study. * Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2 Exclusion 1. Use of a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, alfacalcidiol, and paricalcitol) within 14 days prior to Screening Visit 2; washout will take place during the Screening Period 2. Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take place during the Screening Period 3. Use of calcimimetics, aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, and thiazides within 7 days prior to Screening Visit 1 4. Use of growth hormone therapy within 3 months before Screening Visit 1 5. Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1 6. Presence of nephrocalcinosis on renal ultrasound graded ≥ 3 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 7. Planned or recommended orthopedic surgery, including staples, 8-plates or osteotomy, within the clinical trial period 8. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits \* 9. Evidence of tertiary hyperparathyroidism as determined by the Investigator 10. Use of medication to suppress parathyroid hormone (PTH) (e.g. Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening Visit 1 11. Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study 12. Presence of a concurrent disease or condition that would interfere with study participation or affect safety 13. Previously diagnosed with human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody 14. History of recurrent infection or predisposition to infection, or of known immunodeficiency 15. Use of a therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 or history of allergic or anaphylactic reactions to any monoclonal antibody 16. Presence or history of any hypersensitivity to recombinant human immunoglobulin G1 (IgG1) monoclonal antibody to FGF23 (burosumab) excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects 17. 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 * Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in RSS Total Score Over Time | Baseline, Week 40, 64, 160 | 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. |
| Change From Baseline in Serum Phosphorus Over Time | Baseline, Week 40, 64, 160 | — |
| Change From Baseline in Serum 1,25(OH)2D Over Time | Baseline, Week 40, 64, 160 | — |
| Change From Baseline in TmP/GFR Over Time | Baseline, Week 40, 64, 160 | Data for urinary phosphorus and TRP were used in calculation TmP/GFR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| RGI-C Wrist Scores Over Time | Baseline, Week 40, 64, 160 | 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). |
| Change From Baseline in Growth Velocity Over Time | Baseline, Week 40, 64, 160 | — |
| Change From Baseline in Standing Height Z Score Over Time | Baseline, Week 40, 64, 160 | 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 in Growth (Standing Height) Over Time | Baseline, Week 40, 64, 160 | — |
| Change From Baseline in Growth (Sitting Height) Over Time | Baseline, Week 40, 64, 160 | — |
| Change From Baseline in Growth (Arm Length) Over Time | Baseline, Week 40, 64, 160 | — |
| Change From Baseline in Growth (Leg Length) Over Time | Baseline, Week 40, 64, 160 | — |
| 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | Baseline, Week 40, 64, 160 | The total distance walked (meters) in a 6-minute period was measured. The percent of predicted values were calculated using published normative data based on age, gender, and height (Geiger et al. 2007). |
| Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | Baseline, Week 40, 64, 160 | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. |
| Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | Baseline, Week 40, 64, 160 | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. |
| Change From Baseline in RSS Knee Scores Over Time | Baseline, Week 40, 64, 160 | 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. |
| Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | Baseline, Week 40, 64, 160 | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. |
| Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | Baseline, Week 40, 64, 160 | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. |
| Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | Baseline, Week 40, 64, 160 | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. |
| Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | Baseline, Week 40, 64, 160 | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. |
| Change From Baseline in P1NP Over Time | Baseline, Week 40, 64 | — |
| Change From Baseline in CTx Over Time | Baseline, Week 40, 64 | — |
| Change From Baseline in ALP Over Time | Baseline, Week 40, 64, 160 | — |
| Change From Baseline in BALP Over Time | Baseline, Week 40, 64, 160 | — |
| Serum Pre-Dose Concentrations of Burosumab | Week 40, 64, 160 | — |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Up to 216 weeks | An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE is defined as an AE or suspected adverse reaction that at any dose results in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect. Severity was graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). TEAEs are defined as AEs with onset on or after the time of initiation of study drug administration. |
| Change From Baseline in FEP Over Time | Baseline, Week 40, 64, 160 | FEP is defined as 100% × (urine phosphorus × serum creatinine)/(urine creatinine × serum phosphorus), where the 2-hour urine sample was used for urine phosphorus and urine creatinine. |
| Change From Baseline in RSS Wrist Scores Over Time | Baseline, Week 40, 64, 160 | 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. |
| Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Baseline, Week 40, 64, 160 | 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). |
| RGI-C Knee Scores Over Time | Baseline, Week 40, 64, 160 | 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). |
Countries
France, Netherlands, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Burosumab Q2W Burosumab SC injections every 2 weeks (Q2W). Dose is determined by the participant's weight and prescribed dose by their study doctor. | 26 |
| Burosumab Q4W Then Q2W Burosumab subcutaneous (SC) injections every 4 weeks (Q4W). Dose is determined by the participant's weight and prescribed dose by their study doctor. Participants in Q4W were to switch to Q2W beginning with Week 64 dosing. | 26 |
| Total | 52 |
Baseline characteristics
| Characteristic | Burosumab Q4W Then Q2W | Burosumab Q2W | Total |
|---|---|---|---|
| 6-Minute Walk Test (6MWT) Distance (Predicted Percent of Normal) | 81.42 percentage of predicted distance STANDARD_DEVIATION 15.101 | 79.32 percentage of predicted distance STANDARD_DEVIATION 13.257 | 80.37 percentage of predicted distance STANDARD_DEVIATION 14.109 |
| Age, Continuous | 8.3 years STANDARD_DEVIATION 2.04 | 8.7 years STANDARD_DEVIATION 1.72 | 8.5 years STANDARD_DEVIATION 1.87 |
| Alkaline Phosphatase (ALP) | 456.08 U/L STANDARD_DEVIATION 101.157 | 461.92 U/L STANDARD_DEVIATION 110.209 | 459.00 U/L STANDARD_DEVIATION 104.779 |
| Bone Specific Alkaline Phosphatase (BALP) | 165.62 mcg/L STANDARD_DEVIATION 45.534 | 163.54 mcg/L STANDARD_DEVIATION 58.61 | 164.58 mcg/L STANDARD_DEVIATION 51.814 |
| Burosumab Concentration | 25.00 ng/mL STANDARD_DEVIATION 0 | 25.00 ng/mL STANDARD_DEVIATION 0 | 25.00 ng/mL STANDARD_DEVIATION 0 |
| Carboxy-Terminal Crosslinked Telopeptide of Type I Collagen (CTx) | 2.10 ng/mL STANDARD_DEVIATION 0.679 | 2.23 ng/mL STANDARD_DEVIATION 0.642 | 2.16 ng/mL STANDARD_DEVIATION 0.658 |
| Fractional Excretion of Phosphorus (FEP) | 15.42 percentage of phosphorus excreted STANDARD_DEVIATION 7.373 | 13.91 percentage of phosphorus excreted STANDARD_DEVIATION 6.775 | 14.68 percentage of phosphorus excreted STANDARD_DEVIATION 7.056 |
| Growth (Standing Height, Sitting Height, Arm Length, Leg Length) Arm Length | 52.59 cm STANDARD_DEVIATION 6.129 | 54.80 cm STANDARD_DEVIATION 4.93 | 53.70 cm STANDARD_DEVIATION 5.619 |
| Growth (Standing Height, Sitting Height, Arm Length, Leg Length) Leg Length | 63.71 cm STANDARD_DEVIATION 8.322 | 66.06 cm STANDARD_DEVIATION 7.027 | 64.89 cm STANDARD_DEVIATION 7.718 |
| Growth (Standing Height, Sitting Height, Arm Length, Leg Length) Sitting Height | 67.04 cm STANDARD_DEVIATION 5.691 | 70.10 cm STANDARD_DEVIATION 5.632 | 68.57 cm STANDARD_DEVIATION 5.815 |
| Growth (Standing Height, Sitting Height, Arm Length, Leg Length) Standing Height | 119.42 cm STANDARD_DEVIATION 12.623 | 123.28 cm STANDARD_DEVIATION 10.326 | 121.35 cm STANDARD_DEVIATION 11.584 |
| Growth Velocity | 5.24 cm/year STANDARD_DEVIATION 1.402 | 5.45 cm/year STANDARD_DEVIATION 1.171 | 5.35 cm/year STANDARD_DEVIATION 1.28 |
| POSNA-PODCI Normative Scores Global Functioning Scale | 35.6 T-score STANDARD_DEVIATION 17.24 | 37.5 T-score STANDARD_DEVIATION 13.96 | 36.6 T-score STANDARD_DEVIATION 15.52 |
| POSNA-PODCI Normative Scores Happiness Scale | 43.4 T-score STANDARD_DEVIATION 13.69 | 43.6 T-score STANDARD_DEVIATION 13.75 | 43.5 T-score STANDARD_DEVIATION 13.58 |
| POSNA-PODCI Normative Scores Pain/Comfort Scale | 34.8 T-score STANDARD_DEVIATION 16.76 | 35.2 T-score STANDARD_DEVIATION 15.26 | 35.0 T-score STANDARD_DEVIATION 15.85 |
| POSNA-PODCI Normative Scores Sports/Physical Functioning Scale | 32.2 T-score STANDARD_DEVIATION 19.29 | 34.6 T-score STANDARD_DEVIATION 15.7 | 33.4 T-score STANDARD_DEVIATION 17.42 |
| POSNA-PODCI Normative Scores Transfer and Basic Mobility Scale | 46.0 T-score STANDARD_DEVIATION 10.53 | 45.7 T-score STANDARD_DEVIATION 10.88 | 45.8 T-score STANDARD_DEVIATION 10.61 |
| POSNA-PODCI Normative Scores Upper Extremity Scale | 48.5 T-score STANDARD_DEVIATION 13.04 | 52.1 T-score STANDARD_DEVIATION 6.77 | 50.3 T-score STANDARD_DEVIATION 10.39 |
| Procollagen Type 1 N Propeptide (P1NP) | 742.35 ng/mL STANDARD_DEVIATION 209.727 | 843.11 ng/mL STANDARD_DEVIATION 214.367 | 790.72 ng/mL STANDARD_DEVIATION 215.864 |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 24 Participants | 26 Participants | 50 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 23 Participants | 23 Participants | 46 Participants |
| Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate(TmP/GFR) | 1.978 mg/dL STANDARD_DEVIATION 0.3474 | 2.176 mg/dL STANDARD_DEVIATION 0.4925 | 2.077 mg/dL STANDARD_DEVIATION 0.4335 |
| Rickets Severity Score (RSS) Total Score | 1.67 score on a scale STANDARD_DEVIATION 0.999 | 1.92 score on a scale STANDARD_DEVIATION 1.172 | 1.80 score on a scale STANDARD_DEVIATION 1.086 |
| RSS Knee and Wrist Scores Knee Score | 1.19 score on a scale STANDARD_DEVIATION 0.601 | 1.21 score on a scale STANDARD_DEVIATION 0.681 | 1.20 score on a scale STANDARD_DEVIATION 0.636 |
| RSS Knee and Wrist Scores Wrist Score | 0.48 score on a scale STANDARD_DEVIATION 0.519 | 0.71 score on a scale STANDARD_DEVIATION 0.619 | 0.60 score on a scale STANDARD_DEVIATION 0.578 |
| Serum 1, 25-Dihydroxyvitamin D | 41.37 pg/mL STANDARD_DEVIATION 15.293 | 41.28 pg/mL STANDARD_DEVIATION 21.967 | 41.33 pg/mL STANDARD_DEVIATION 18.74 |
| Serum Phosphorus | 2.28 mg/dL STANDARD_DEVIATION 0.299 | 2.38 mg/dL STANDARD_DEVIATION 0.405 | 2.33 mg/dL STANDARD_DEVIATION 0.356 |
| Sex: Female, Male Female | 14 Participants | 14 Participants | 28 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 24 Participants |
| Standing Height Z-Score | -2.05 Z score STANDARD_DEVIATION 0.957 | -1.72 Z score STANDARD_DEVIATION 1.026 | -1.89 Z score STANDARD_DEVIATION 0.996 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 26 / 26 | 26 / 26 |
| serious Total, serious adverse events | 0 / 26 | 1 / 26 |
Outcome results
Primary
Change From Baseline in RSS Total Score Over Time
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.
Time frame: Baseline, Week 40, 64, 160
Population: Intent to Treat (ITT) Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in RSS Total Score Over Time | Change to Week 40 | -1.06 score on a scale | Standard Error 0.1 |
| Burosumab Q2W | Change From Baseline in RSS Total Score Over Time | Change to Week 64 | -1.00 score on a scale | Standard Error 0.11 |
| Burosumab Q2W | Change From Baseline in RSS Total Score Over Time | Change to Week 160 | -0.98 score on a scale | Standard Error 0.129 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Total Score Over Time | Change to Week 40 | -0.73 score on a scale | Standard Error 0.1 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Total Score Over Time | Change to Week 64 | -0.84 score on a scale | Standard Error 0.098 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Total Score Over Time | Change to Week 160 | -0.83 score on a scale | Standard Error 0.122 |
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Difference in change to Week 4095% CI: [-0.63, -0.04]
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Difference in change to Week 6495% CI: [-0.45, 0.13]
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Primary
Change From Baseline in Serum 1,25(OH)2D Over Time
Time frame: Baseline, Week 40, 64, 160
Population: PK/PD Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Serum 1,25(OH)2D Over Time | Change at Week 40 | 28.27 pg/mL | Standard Deviation 29.312 |
| Burosumab Q2W | Change From Baseline in Serum 1,25(OH)2D Over Time | Change at Week 64 | 23.58 pg/mL | Standard Deviation 24.502 |
| Burosumab Q2W | Change From Baseline in Serum 1,25(OH)2D Over Time | Change at Week 160 | 17.03 pg/mL | Standard Deviation 24.889 |
| Burosumab Q4W Then Q2W | Change From Baseline in Serum 1,25(OH)2D Over Time | Change at Week 40 | 17.62 pg/mL | Standard Deviation 18.802 |
| Burosumab Q4W Then Q2W | Change From Baseline in Serum 1,25(OH)2D Over Time | Change at Week 64 | 11.50 pg/mL | Standard Deviation 16.522 |
| Burosumab Q4W Then Q2W | Change From Baseline in Serum 1,25(OH)2D Over Time | Change at Week 160 | 19.64 pg/mL | Standard Deviation 22.857 |
Comparison: Week 40p-value: <0.0001one sample t test
Comparison: Week 40p-value: <0.0001one sample t test
Comparison: Week 64p-value: <0.0001one sample t test
Comparison: Week 64p-value: 0.0024one sample t test
Comparison: Week 160p-value: 0.0018one sample t test
Comparison: Week 160p-value: 0.0002one sample t test
Primary
Change From Baseline in Serum Phosphorus Over Time
Time frame: Baseline, Week 40, 64, 160
Population: Pharmacokinetic/Pharamcodynamic (PK/PD) Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Serum Phosphorus Over Time | Change at Week 40 | 0.92 mg/dL | Standard Deviation 0.48 |
| Burosumab Q2W | Change From Baseline in Serum Phosphorus Over Time | Change at Week 64 | 0.99 mg/dL | Standard Deviation 0.502 |
| Burosumab Q2W | Change From Baseline in Serum Phosphorus Over Time | Change at Week 160 | 0.97 mg/dL | Standard Deviation 0.338 |
| Burosumab Q4W Then Q2W | Change From Baseline in Serum Phosphorus Over Time | Change at Week 40 | 0.57 mg/dL | Standard Deviation 0.265 |
| Burosumab Q4W Then Q2W | Change From Baseline in Serum Phosphorus Over Time | Change at Week 64 | 0.69 mg/dL | Standard Deviation 0.37 |
| Burosumab Q4W Then Q2W | Change From Baseline in Serum Phosphorus Over Time | Change at Week 160 | 1.08 mg/dL | Standard Deviation 0.377 |
Comparison: Week 40p-value: <0.0001one sample t test
Comparison: Week 40p-value: <0.0001one sample t test
Comparison: Week 64p-value: <0.0001one sample t test
Comparison: Week 64p-value: <0.0001one sample t test
Comparison: Week 160p-value: <0.0001one sample t test
Comparison: Week 160p-value: <0.0001one sample t test
Primary
Change From Baseline in TmP/GFR Over Time
Data for urinary phosphorus and TRP were used in calculation TmP/GFR.
Time frame: Baseline, Week 40, 64, 160
Population: PK/PD Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in TmP/GFR Over Time | Change at Week 40 | 1.14 mg/dL | Standard Deviation 0.686 |
| Burosumab Q2W | Change From Baseline in TmP/GFR Over Time | Change at Week 64 | 1.11 mg/dL | Standard Deviation 0.626 |
| Burosumab Q2W | Change From Baseline in TmP/GFR Over Time | Change at Week 160 | 1.24 mg/dL | Standard Deviation 0.548 |
| Burosumab Q4W Then Q2W | Change From Baseline in TmP/GFR Over Time | Change at Week 40 | 0.80 mg/dL | Standard Deviation 0.506 |
| Burosumab Q4W Then Q2W | Change From Baseline in TmP/GFR Over Time | Change at Week 64 | 0.90 mg/dL | Standard Deviation 0.632 |
| Burosumab Q4W Then Q2W | Change From Baseline in TmP/GFR Over Time | Change at Week 160 | 1.45 mg/dL | Standard Deviation 0.653 |
Comparison: Week 40p-value: <0.0001one sample t test
Comparison: Week 40p-value: <0.0001one sample t test
Comparison: Week 64p-value: <0.0001one sample t test
Comparison: Week 64p-value: <0.0001one sample t test
Comparison: Week 160p-value: <0.0001one sample t test
Comparison: Week 160p-value: <0.0001one sample t test
Secondary
6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time
The total distance walked (meters) in a 6-minute period was measured. The percent of predicted values were calculated using published normative data based on age, gender, and height (Geiger et al. 2007).
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | Change to Week 40 | 3.25 percentage of predicted distance | Standard Error 1.841 |
| Burosumab Q2W | 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | Change to Week 64 | 5.29 percentage of predicted distance | Standard Error 1.568 |
| Burosumab Q2W | 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | Change to Week 160 | 1.96 percentage of predicted distance | Standard Error 1.483 |
| Burosumab Q4W Then Q2W | 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | Change to Week 40 | 0.24 percentage of predicted distance | Standard Error 2.153 |
| Burosumab Q4W Then Q2W | 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | Change to Week 64 | 3.70 percentage of predicted distance | Standard Error 1.731 |
| Burosumab Q4W Then Q2W | 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | Change to Week 160 | 2.15 percentage of predicted distance | Standard Error 1.932 |
Comparison: Week 40p-value: 0.0771GEE model
Comparison: Week 40p-value: 0.9098GEE model
Comparison: Week 64p-value: 0.0007GEE model
Comparison: Week 64p-value: 0.0327GEE model
Comparison: Week 160p-value: 0.1865GEE model
Comparison: Week 160p-value: 0.2654GEE model
Secondary
Change From Baseline in ALP Over Time
Time frame: Baseline, Week 40, 64, 160
Population: PK/PD Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in ALP Over Time | Change at Week 40 | -79.4 U/L | Standard Deviation 97.4 |
| Burosumab Q2W | Change From Baseline in ALP Over Time | Change at Week 64 | -113.9 U/L | Standard Deviation 81.28 |
| Burosumab Q2W | Change From Baseline in ALP Over Time | Change at Week 160 | -153.1 U/L | Standard Deviation 132.45 |
| Burosumab Q4W Then Q2W | Change From Baseline in ALP Over Time | Change at Week 40 | -47.8 U/L | Standard Deviation 70.86 |
| Burosumab Q4W Then Q2W | Change From Baseline in ALP Over Time | Change at Week 64 | -80.9 U/L | Standard Deviation 67.11 |
| Burosumab Q4W Then Q2W | Change From Baseline in ALP Over Time | Change at Week 160 | -140.0 U/L | Standard Deviation 115.82 |
Comparison: Week 40p-value: 0.0003one sample t test
Comparison: Week 40p-value: 0.0021one sample t test
Comparison: Week 64p-value: <0.0001one sample t test
Comparison: Week 64p-value: <0.0001one sample t test
Comparison: Week 160p-value: <0.0001one sample t test
Comparison: Week 160p-value: <0.0001one sample t test
Secondary
Change From Baseline in BALP Over Time
Time frame: Baseline, Week 40, 64, 160
Population: PK/PD Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in BALP Over Time | Change at Week 40 | -35.55 mcg/L | Standard Deviation 46.738 |
| Burosumab Q2W | Change From Baseline in BALP Over Time | Change at Week 64 | -50.40 mcg/L | Standard Deviation 36.478 |
| Burosumab Q2W | Change From Baseline in BALP Over Time | Change at Week 160 | -67.25 mcg/L | Standard Deviation 59.309 |
| Burosumab Q4W Then Q2W | Change From Baseline in BALP Over Time | Change at Week 40 | -27.80 mcg/L | Standard Deviation 31.409 |
| Burosumab Q4W Then Q2W | Change From Baseline in BALP Over Time | Change at Week 64 | -47.13 mcg/L | Standard Deviation 28.822 |
| Burosumab Q4W Then Q2W | Change From Baseline in BALP Over Time | Change at Week 160 | -56.73 mcg/L | Standard Deviation 52.284 |
Secondary
Change From Baseline in CTx Over Time
Time frame: Baseline, Week 40, 64
Population: PK/PD Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in CTx Over Time | Change at Week 40 | 1.01 ng/mL | Standard Deviation 0.802 |
| Burosumab Q2W | Change From Baseline in CTx Over Time | Change at Week 64 | 1.08 ng/mL | Standard Deviation 0.87 |
| Burosumab Q4W Then Q2W | Change From Baseline in CTx Over Time | Change at Week 40 | 0.64 ng/mL | Standard Deviation 0.578 |
| Burosumab Q4W Then Q2W | Change From Baseline in CTx Over Time | Change at Week 64 | 0.81 ng/mL | Standard Deviation 0.706 |
Secondary
Change From Baseline in FEP Over Time
FEP is defined as 100% × (urine phosphorus × serum creatinine)/(urine creatinine × serum phosphorus), where the 2-hour urine sample was used for urine phosphorus and urine creatinine.
Time frame: Baseline, Week 40, 64, 160
Population: Safety Analysis Set: All participants who received at least 1 dose of study therapy and had an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in FEP Over Time | Change at Week 40 | -3.97 percentage of phosphorus excreted | Standard Deviation 7.161 |
| Burosumab Q2W | Change From Baseline in FEP Over Time | Change at Week 64 | -2.63 percentage of phosphorus excreted | Standard Deviation 4.446 |
| Burosumab Q2W | Change From Baseline in FEP Over Time | Change at Week 160 | -5.43 percentage of phosphorus excreted | Standard Deviation 6.985 |
| Burosumab Q4W Then Q2W | Change From Baseline in FEP Over Time | Change at Week 40 | -4.85 percentage of phosphorus excreted | Standard Deviation 7.17 |
| Burosumab Q4W Then Q2W | Change From Baseline in FEP Over Time | Change at Week 64 | -3.96 percentage of phosphorus excreted | Standard Deviation 7.522 |
| Burosumab Q4W Then Q2W | Change From Baseline in FEP Over Time | Change at Week 160 | -6.47 percentage of phosphorus excreted | Standard Deviation 8.072 |
Secondary
Change From Baseline in Growth (Arm Length) Over Time
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Growth (Arm Length) Over Time | Change at Week 40 | 2.36 cm | Standard Deviation 1.058 |
| Burosumab Q2W | Change From Baseline in Growth (Arm Length) Over Time | Change at Week 64 | 3.99 cm | Standard Deviation 1.556 |
| Burosumab Q2W | Change From Baseline in Growth (Arm Length) Over Time | Change at Week 160 | 8.50 cm | Standard Deviation 1.537 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Arm Length) Over Time | Change at Week 40 | 2.08 cm | Standard Deviation 0.905 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Arm Length) Over Time | Change at Week 64 | 4.77 cm | Standard Deviation 7.382 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Arm Length) Over Time | Change at Week 160 | 8.32 cm | Standard Deviation 1.798 |
Secondary
Change From Baseline in Growth (Leg Length) Over Time
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Growth (Leg Length) Over Time | Change to Week 40 | 2.90 cm | Standard Deviation 1.365 |
| Burosumab Q2W | Change From Baseline in Growth (Leg Length) Over Time | Change at Week 64 | 5.03 cm | Standard Deviation 1.879 |
| Burosumab Q2W | Change From Baseline in Growth (Leg Length) Over Time | Change at Week 160 | 11.78 cm | Standard Deviation 3.04 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Leg Length) Over Time | Change to Week 40 | 2.82 cm | Standard Deviation 1.27 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Leg Length) Over Time | Change at Week 64 | 5.16 cm | Standard Deviation 1.283 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Leg Length) Over Time | Change at Week 160 | 11.67 cm | Standard Deviation 2.338 |
Secondary
Change From Baseline in Growth (Sitting Height) Over Time
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Growth (Sitting Height) Over Time | Change at Week 40 | 2.66 cm | Standard Deviation 5.496 |
| Burosumab Q2W | Change From Baseline in Growth (Sitting Height) Over Time | Change at Week 64 | 3.08 cm | Standard Deviation 2.405 |
| Burosumab Q2W | Change From Baseline in Growth (Sitting Height) Over Time | Change at Week 160 | 8.29 cm | Standard Deviation 2.928 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Sitting Height) Over Time | Change at Week 40 | 2.39 cm | Standard Deviation 1.486 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Sitting Height) Over Time | Change at Week 64 | 3.45 cm | Standard Deviation 1.39 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Sitting Height) Over Time | Change at Week 160 | 8.62 cm | Standard Deviation 2.163 |
Secondary
Change From Baseline in Growth (Standing Height) Over Time
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Growth (Standing Height) Over Time | Change at Week 40 | 5.03 cm | Standard Deviation 1.232 |
| Burosumab Q2W | Change From Baseline in Growth (Standing Height) Over Time | Change at Week 64 | 7.48 cm | Standard Deviation 1.934 |
| Burosumab Q2W | Change From Baseline in Growth (Standing Height) Over Time | Change at Week 160 | 18.38 cm | Standard Deviation 2.958 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Standing Height) Over Time | Change at Week 40 | 4.49 cm | Standard Deviation 1.455 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Standing Height) Over Time | Change at Week 64 | 6.98 cm | Standard Deviation 1.594 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth (Standing Height) Over Time | Change at Week 160 | 17.22 cm | Standard Deviation 2.653 |
Secondary
Change From Baseline in Growth Velocity Over Time
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Growth Velocity Over Time | Week 0 to Week 40: Change from Baseline | 0.96 cm/year | Standard Deviation 1.677 |
| Burosumab Q2W | Change From Baseline in Growth Velocity Over Time | Week 0 to Week 64: Change from Baseline | 0.73 cm/year | Standard Deviation 1.399 |
| Burosumab Q2W | Change From Baseline in Growth Velocity Over Time | Week 64 to Week 112: Change from Baseline | 0.29 cm/year | Standard Deviation 2.284 |
| Burosumab Q2W | Change From Baseline in Growth Velocity Over Time | Week 112 to Week 160: Change from Baseline | 0.67 cm/year | Standard Deviation 2.318 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth Velocity Over Time | Week 112 to Week 160: Change from Baseline | 0.54 cm/year | Standard Deviation 3.158 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth Velocity Over Time | Week 0 to Week 40: Change from Baseline | 0.39 cm/year | Standard Deviation 2.559 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth Velocity Over Time | Week 64 to Week 112: Change from Baseline | 0.09 cm/year | Standard Deviation 2.523 |
| Burosumab Q4W Then Q2W | Change From Baseline in Growth Velocity Over Time | Week 0 to Week 64: Change from Baseline | 0.37 cm/year | Standard Deviation 2.164 |
Comparison: Week 0 to Week 40p-value: 0.0088one sample t-test
Comparison: Week 0 to Week 40p-value: 0.465one sample t-test
Comparison: Week 0 to Week 64p-value: 0.016one sample t test
Comparison: Week 0 to Week 64p-value: 0.4114one sample t test
Comparison: Week 64 to Week 112p-value: 0.5335one sample t test
Comparison: Week 64 to Week 112p-value: 0.8606one sample t test
Comparison: Week 112 to Week 160p-value: 0.1627one sample t test
Comparison: Week 112 to Week 160p-value: 0.4096one sample t test
Secondary
Change From Baseline in P1NP Over Time
Time frame: Baseline, Week 40, 64
Population: PK/PD Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in P1NP Over Time | Change at Week 40 | 275.98 ng/mL | Standard Deviation 329.587 |
| Burosumab Q2W | Change From Baseline in P1NP Over Time | Change at Week 64 | 137.35 ng/mL | Standard Deviation 354.315 |
| Burosumab Q4W Then Q2W | Change From Baseline in P1NP Over Time | Change at Week 40 | 224.91 ng/mL | Standard Deviation 161.053 |
| Burosumab Q4W Then Q2W | Change From Baseline in P1NP Over Time | Change at Week 64 | 133.56 ng/mL | Standard Deviation 192.306 |
Secondary
Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | Change at Week 40 | 9.06 T-score | Standard Error 1.56 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | Change at Week 64 | 6.02 T-score | Standard Error 2.706 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | Change at Week 160 | 11.37 T-score | Standard Error 1.804 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | Change at Week 40 | 8.12 T-score | Standard Error 2.351 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | Change at Week 64 | 8.72 T-score | Standard Error 2.019 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | Change at Week 160 | 11.94 T-score | Standard Error 2.024 |
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Week 40p-value: 0.0006GEE model
Comparison: Week 64p-value: 0.026GEE model
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | Change at Week 40 | 2.84 T-score | Standard Error 2.328 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | Change at Week 64 | 2.18 T-score | Standard Error 1.914 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | Change at Week 160 | 6.46 T-score | Standard Error 2.486 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | Change at Week 40 | 3.01 T-score | Standard Error 1.902 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | Change at Week 64 | 3.34 T-score | Standard Error 1.914 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | Change at Week 160 | 9.19 T-score | Standard Error 1.075 |
Comparison: Week 40p-value: 0.223GEE model
Comparison: Week 40p-value: 0.1132GEE model
Comparison: Week 64p-value: 0.2558GEE model
Comparison: Week 64p-value: 0.0814GEE model
Comparison: Week 160p-value: 0.0093GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | Change at Week 40 | 7.67 T-score | Standard Error 2.399 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | Change at Week 64 | 5.60 T-score | Standard Error 2.904 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | Change at Week 160 | 13.06 T-score | Standard Error 2.187 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | Change at Week 40 | 7.39 T-score | Standard Error 2.477 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | Change at Week 64 | 7.74 T-score | Standard Error 2.077 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | Change at Week 160 | 12.38 T-score | Standard Error 2.265 |
Comparison: Week 40p-value: 0.0014GEE model
Comparison: Week 40p-value: 0.0028GEE model
Comparison: Week 64p-value: 0.0536GEE model
Comparison: Week 64p-value: 0.0002GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | Change at Week 40 | 9.78 T-score | Standard Error 1.679 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | Change at Week 64 | 7.74 T-score | Standard Error 2.636 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | Change at Week 160 | 12.04 T-score | Standard Error 2.102 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | Change at Week 40 | 9.15 T-score | Standard Error 2.249 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | Change at Week 64 | 9.84 T-score | Standard Error 2.534 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | Change at Week 160 | 14.33 T-score | Standard Error 1.834 |
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Week 64p-value: 0.0033GEE model
Comparison: Week 64p-value: 0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | Change at Week 40 | 4.04 T-score | Standard Error 0.827 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | Change at Week 64 | -0.34 T-score | Standard Error 3.123 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | Change at Week 160 | 1.88 T-score | Standard Error 3.285 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | Change at Week 40 | 3.69 T-score | Standard Error 1.648 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | Change at Week 64 | 4.32 T-score | Standard Error 1.364 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | Change at Week 160 | 5.44 T-score | Standard Error 1.113 |
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Week 40p-value: 0.0251GEE model
Comparison: Week 64p-value: 0.9124GEE model
Comparison: Week 64p-value: 0.0016GEE model
Comparison: Week 160p-value: 0.5677GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | Change at Week 40 | 2.97 T-score | Standard Error 0.71 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | Change at Week 64 | 1.89 T-score | Standard Error 0.914 |
| Burosumab Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | Change at Week 160 | -0.02 T-score | Standard Error 0.74 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | Change at Week 40 | 2.97 T-score | Standard Error 1.212 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | Change at Week 64 | 3.20 T-score | Standard Error 0.911 |
| Burosumab Q4W Then Q2W | Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | Change at Week 160 | 1.82 T-score | Standard Error 1.449 |
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Week 40p-value: 0.0144GEE model
Comparison: Week 64p-value: 0.0384GEE model
Comparison: Week 64p-value: 0.0004GEE model
Comparison: Week 160p-value: 0.9795GEE model
Comparison: Week 160p-value: 0.2082GEE model
Secondary
Change From Baseline in RSS Knee Scores Over Time
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in RSS Knee Scores Over Time | Change at Week 40 | -0.62 score on a scale | Standard Error 0.08 |
| Burosumab Q2W | Change From Baseline in RSS Knee Scores Over Time | Change at Week 64 | -0.70 score on a scale | Standard Error 0.087 |
| Burosumab Q2W | Change From Baseline in RSS Knee Scores Over Time | Change at Week 160 | -0.70 score on a scale | Standard Error 0.105 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Knee Scores Over Time | Change at Week 40 | -0.55 score on a scale | Standard Error 0.08 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Knee Scores Over Time | Change at Week 64 | -0.61 score on a scale | Standard Error 0.072 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Knee Scores Over Time | Change at Week 160 | -0.62 score on a scale | Standard Error 0.093 |
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Change From Baseline in RSS Wrist Scores Over Time
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in RSS Wrist Scores Over Time | Change at Week 40 | -0.44 score on a scale | Standard Error 0.05 |
| Burosumab Q2W | Change From Baseline in RSS Wrist Scores Over Time | Change at Week 64 | -0.30 score on a scale | Standard Error 0.057 |
| Burosumab Q2W | Change From Baseline in RSS Wrist Scores Over Time | Change at Week 160 | -0.27 score on a scale | Standard Error 0.065 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Wrist Scores Over Time | Change at Week 40 | -0.18 score on a scale | Standard Error 0.05 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Wrist Scores Over Time | Change at Week 64 | -0.24 score on a scale | Standard Error 0.051 |
| Burosumab Q4W Then Q2W | Change From Baseline in RSS Wrist Scores Over Time | Change at Week 160 | -0.20 score on a scale | Standard Error 0.047 |
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 40p-value: 0.0015ANCOVA
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Change From Baseline in Standing Height Z Score Over Time
Standing height Z scores are measures of height adjusted for a child's age and sex. The Z score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome.
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Change From Baseline in Standing Height Z Score Over Time | Change to Week 40 | 0.17 Z score | Standard Error 0.042 |
| Burosumab Q2W | Change From Baseline in Standing Height Z Score Over Time | Change to Week 64 | 0.19 Z score | Standard Error 0.051 |
| Burosumab Q2W | Change From Baseline in Standing Height Z Score Over Time | Change to Week 160 | 0.35 Z score | Standard Error 0.084 |
| Burosumab Q4W Then Q2W | Change From Baseline in Standing Height Z Score Over Time | Change to Week 40 | 0.10 Z score | Standard Error 0.051 |
| Burosumab Q4W Then Q2W | Change From Baseline in Standing Height Z Score Over Time | Change to Week 64 | 0.12 Z score | Standard Error 0.061 |
| Burosumab Q4W Then Q2W | Change From Baseline in Standing Height Z Score Over Time | Change to Week 160 | 0.19 Z score | Standard Error 0.089 |
Comparison: Week 40p-value: <0.0001GEE model
Comparison: Week 40p-value: 0.0569GEE model
Comparison: Week 64p-value: 0.0002GEE model
Comparison: Week 64p-value: 0.0456GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: 0.0343GEE model
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE is defined as an AE or suspected adverse reaction that at any dose results in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect. Severity was graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). TEAEs are defined as AEs with onset on or after the time of initiation of study drug administration.
Time frame: Up to 216 weeks
Population: Safety Analysis Set: All participants who received at least 1 dose of study therapy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | All TEAEs | 26 Participants |
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Grade 3 or 4 TEAE | 1 Participants |
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Related TEAE | 17 Participants |
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Serious TEAE | 0 Participants |
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | TEAE Leading to Treatment Discontinuation | 0 Participants |
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Serious Related TEAE | 0 Participants |
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | TEAE Leading to Death | 0 Participants |
| Burosumab Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | TEAE Leading to Study Discontinuation | 0 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | TEAE Leading to Death | 0 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | All TEAEs | 26 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Serious TEAE | 1 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Related TEAE | 21 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Serious Related TEAE | 1 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | Grade 3 or 4 TEAE | 1 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | TEAE Leading to Study Discontinuation | 0 Participants |
| Burosumab Q4W Then Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | TEAE Leading to Treatment Discontinuation | 0 Participants |
Secondary
Radiographic Global Impression of Change (RGI-C) Global Scores Over Time
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).
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Change at Week 40 | 1.67 score on a scale | Standard Error 0.12 |
| Burosumab Q2W | Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Change at Week 64 | 1.56 score on a scale | Standard Error 0.112 |
| Burosumab Q2W | Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Change at Week 160 | 1.92 score on a scale | Standard Error 0.111 |
| Burosumab Q4W Then Q2W | Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Change at Week 40 | 1.46 score on a scale | Standard Error 0.12 |
| Burosumab Q4W Then Q2W | Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Change at Week 64 | 1.58 score on a scale | Standard Error 0.112 |
| Burosumab Q4W Then Q2W | Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Change at Week 160 | 1.86 score on a scale | Standard Error 0.119 |
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Difference in change to Week 4095% CI: [-0.12, 0.54]
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Difference in change to Week 6495% CI: [-0.34, 0.29]
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
RGI-C Knee Scores Over Time
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).
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | RGI-C Knee Scores Over Time | Change at Week 40 | 1.60 score on a scale | Standard Error 0.13 |
| Burosumab Q2W | RGI-C Knee Scores Over Time | Change at Week 64 | 1.57 score on a scale | Standard Error 0.104 |
| Burosumab Q2W | RGI-C Knee Scores Over Time | Change at Week 160 | 2.01 score on a scale | Standard Error 0.106 |
| Burosumab Q4W Then Q2W | RGI-C Knee Scores Over Time | Change at Week 40 | 1.34 score on a scale | Standard Error 0.13 |
| Burosumab Q4W Then Q2W | RGI-C Knee Scores Over Time | Change at Week 64 | 1.53 score on a scale | Standard Error 0.099 |
| Burosumab Q4W Then Q2W | RGI-C Knee Scores Over Time | Change at Week 160 | 1.85 score on a scale | Standard Error 0.118 |
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
RGI-C Wrist Scores Over Time
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).
Time frame: Baseline, Week 40, 64, 160
Population: ITT Analysis Set: all participants who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | RGI-C Wrist Scores Over Time | Change at Week 40 | 1.64 score on a scale | Standard Error 0.14 |
| Burosumab Q2W | RGI-C Wrist Scores Over Time | Change at Week 64 | 1.65 score on a scale | Standard Error 0.153 |
| Burosumab Q2W | RGI-C Wrist Scores Over Time | Change at Week 160 | 1.78 score on a scale | Standard Error 0.133 |
| Burosumab Q4W Then Q2W | RGI-C Wrist Scores Over Time | Change at Week 40 | 1.45 score on a scale | Standard Error 0.14 |
| Burosumab Q4W Then Q2W | RGI-C Wrist Scores Over Time | Change at Week 64 | 1.55 score on a scale | Standard Error 0.124 |
| Burosumab Q4W Then Q2W | RGI-C Wrist Scores Over Time | Change at Week 160 | 1.83 score on a scale | Standard Error 0.132 |
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 40p-value: <0.0001ANCOVA
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 64p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Comparison: Week 160p-value: <0.0001GEE model
Secondary
Serum Pre-Dose Concentrations of Burosumab
Time frame: Week 40, 64, 160
Population: PK/PD Analysis Set: all participants who received at least 1 dose of therapy and had evaluable serum data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab Q2W | Serum Pre-Dose Concentrations of Burosumab | Week 64 | 15846.65 ng/mL | Standard Deviation 9385.393 |
| Burosumab Q2W | Serum Pre-Dose Concentrations of Burosumab | Week 40 | 13188.81 ng/mL | Standard Deviation 7188.588 |
| Burosumab Q2W | Serum Pre-Dose Concentrations of Burosumab | Week 160 | 13975.27 ng/mL | Standard Deviation 8168.877 |
| Burosumab Q4W Then Q2W | Serum Pre-Dose Concentrations of Burosumab | Week 40 | 6443.08 ng/mL | Standard Deviation 3266.215 |
| Burosumab Q4W Then Q2W | Serum Pre-Dose Concentrations of Burosumab | Week 64 | 8525.63 ng/mL | Standard Deviation 3968.821 |
| Burosumab Q4W Then Q2W | Serum Pre-Dose Concentrations of Burosumab | Week 160 | 13163.96 ng/mL | Standard Deviation 6593.12 |