X-Linked Hypophosphatemia
Conditions
Brief summary
The primary objective of this study is to evaluate the effect of KRN23 (burosumab) therapy in improving rickets in children with XLH compared with active control (oral phosphate/active vitamin D).
Interventions
BIOLOGICALburosumab
solution for subcutaneous (SC) injection
DRUGOral Phosphate Supplement
oral tablet; oral solution; oral powder
DRUGactive vitamin D
tablet, oral solution
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
1 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged 1 to ≤12 years with radiographic evidence of rickets as determined by central readers 2. Phosphate-regulating endopeptidase homolog, X-linked (PHEX) mutation or variant of uncertain significance in either the patient or in a directly related family member with appropriate X-linked inheritance 3. Biochemical findings associated with XLH: serum phosphorus \<3.0 mg/dL (\<0.97 mmol/L) 4. Serum creatinine below the age-adjusted upper limit of normal 5. Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit 6. Have received both oral phosphate and active vitamin D therapy for ≥ 12 consecutive months (for children ≥3 years of age) or ≥ 6 consecutive months (for children \<3 years of age) 7 days prior to the Randomization Visit 7. Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history 8. Provide written or verbal assent (as appropriate for the subject and region) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures. 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. Female subjects of childbearing potential must be willing to use a highly effective method of contraception for the duration of the study plus 12 weeks after stopping the study drug. Sexually active male subjects with female partners of childbearing potential must consent to use a condom with spermicide or a highly effective method of contraception for the duration of the study plus 12 weeks after stopping the study drug
Exclusion criteria
1. Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, based on physical examination 2. Height percentile \> 50th based on country-specific norms 3. Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit 4. Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty 5. Use of growth hormone therapy within 12 months before the Screening Visit 6. Presence of nephrocalcinosis on renal ultrasound grade 4 7. Planned orthopedic surgery, including osteotomy or implantation or removal of staples, 8 plates, or any other hardware, within the first 40 weeks of the study 8. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits 9. Evidence of hyperparathyroidism (parathyroid hormone \[PTH\] levels 2.5X upper limit of normal \[ULN\]) 10. Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months prior to the Screening Visit 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. History of recurrent infection or predisposition to infection, or of known immunodeficiency 14. Use of a therapeutic monoclonal antibody within 90 days prior to the Screening Visit or history of allergic or anaphylactic reactions to any monoclonal antibody 15. Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects 16. Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. OR, in Japan, use of any investigational product or investigational medical device within 4 months prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Global Impression of Change (RGI-C) Global Score at Week 40 | Week 40 | Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64 | Week 64 | RGI-C responders are defined as participants with a mean RGI-C global score \>= +2.0. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). |
| RGI-C Global Score at Week 64 | Week 64 | Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). |
| Change From Baseline in RSS Total Score at Week 40 | Baseline, Week 40 | The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, lucency, separation, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees (the total score is the sum of the wrist and knee score). Higher scores indicate greater rickets severity. |
| Change From Baseline in RSS Total Score at Week 64 | Baseline, Week 64 | The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. |
| RGI-C Long Leg Score at Week 40 | Week 40 | Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening). |
| RGI-C Long Leg Score at Week 64 | Week 64 | Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening). |
| Change From Baseline in Height-For-Age Z-Scores to Week 40 | Baseline, Week 40 | Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the Centers for Disease Control \[CDC\] growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. |
| Change From Baseline in Height-For-Age Z-Scores to Week 64 | Baseline, Week 64 | Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. |
| Change in Growth Velocity Z Score From Baseline to Week 40 | Baseline, Week 40 | A growth velocity Z score was calculated based on Tanner's standard. The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for participants who had data available from within 1.5 years prior to baseline. The Week 64 growth velocity was calculated using data between baseline and Week 64. The mid-point of the age interval was used to locate the closest reference age provided by Tanner's Standard. Children with a mid-point age under 2.25 years were excluded, because younger ages are not available in Tanner's standard. To smoothly transition from recumbent length to standing height, 0·8 cm was subtracted from recumbent length before pooling with standing height. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome. |
| Change in Growth Velocity Z Score From Baseline to Week 64 | Baseline, Week 64 | A growth velocity Z score was calculated based on Tanner's standard. The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for participants who had data available from within 1.5 years prior to baseline. The Week 64 growth velocity was calculated using data between baseline and Week 64. The mid-point of the age interval was used to locate the closest reference age provided by Tanner's Standard. Children with a mid-point age under 2.25 years were excluded, because younger ages are not available in Tanner's standard. To smoothly transition from recumbent length to standing height, 0·8 cm was subtracted from recumbent length before pooling with standing height. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome. |
| Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64 | The GEE model includes change from baseline for serum phosphorous measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64. |
| Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Baseline, Weeks 66, 68, 76, 88, 100, 112 | — |
| Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64 | Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64 | The ANCOVA model includes change in serum phosphorus from baseline to mean post-baseline as the dependent variable, treatment group, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate. |
| Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab) | Burosumab arm: Baseline, Week 1, 4, 8, 16, 24, 32, 40, 52, 64, 66, 68, 76, 88, 100, 112, 124, 140; Active Control arm: Baseline, Week 68, 76, 88, 100, 112, 124, 140 | — |
| Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL) | Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140 | — |
| Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40 | Week 40 | RGI-C responders are defined as participants with a mean RGI-C global score \>= +2.0. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). |
| Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Baseline, Weeks 68, 76, 88, 100, 112 | — |
| Change From Baseline Over Time in TmP/GFR, up to Week 64 | Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64 | Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR. The GEE model includes change from baseline for TmP/GFR measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline TmP/GFR measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64. |
| Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Baseline, Weeks 68, 76, 88, 112 | Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR. |
| Change From Baseline Over Time in Serum ALP, up to Week 64 | Baseline, Weeks 16, 24, 40, 52, 64 | The GEE model includes change from baseline for ALP measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline ALP measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64. |
| Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Baseline, Weeks 68, 76, 88, 100, 112 | — |
| Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112 | Decreases indicate improvement. |
| Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Baseline, Week 40 | The PROMIS was developed by the National Institutes of Health and uses domain-specific measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue. |
| Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Baseline, Week 64 | The PROMIS was developed by the National Institutes of Health and uses domain-specific measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue. |
| Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Baseline, Week 40 | The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain. |
| Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Baseline, Week 64 | The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain. |
| Change From Baseline in the 6MWT Total Distance at Week 40 | Baseline, Week 40 | The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test. |
| Change From Baseline in the 6MWT Total Distance at Week 64 | Baseline, Week 64 | The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test. |
| Percent of Predicted Normal in the 6MWT Total Distance at Week 40 | Baseline, Week 40 | The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test, and the percent predicted distance based on normative data for age and gender was estimated. |
| Percent of Predicted Normal in the 6MWT Total Distance at Week 64 | Baseline, Week 64 | The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test, and the percent predicted distance based on normative data for age and gender was estimated. |
| Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64 | The GEE model includes change from baseline for 1, 25-Dihydroxyvitamin D measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline 1, 25-Dihydroxyvitamin D measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64. |
Countries
Australia, Canada, Japan, South Korea, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Eligible participants discontinued oral phosphate and active vitamin D therapy for 7 days prior to randomization. Participants were then randomized 1:1 to receive either open label burosumab administered by subcutaneous (SC) injection every 2 weeks (Q2W) or phosphate and active vitamin D therapy administered orally daily for a total of 64 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Active Control Multiple daily doses of oral phosphate and one or more daily doses of active vitamin D therapy, titrated and individualized by the investigator based on published recommendations during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period. | 32 |
| Burosumab Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period. | 29 |
| Total | 61 |
Baseline characteristics
| Characteristic | Active Control | Burosumab | Total |
|---|---|---|---|
| Age, Continuous | 6.50 years STANDARD_DEVIATION 3.25 | 6.01 years STANDARD_DEVIATION 3.408 | 6.27 years STANDARD_DEVIATION 3.307 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 26 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Faces Pain Scale-Revised (FPS-R) | 0.7 score on a scale STANDARD_DEVIATION 1.17 | 0.4 score on a scale STANDARD_DEVIATION 1.12 | 0.6 score on a scale STANDARD_DEVIATION 1.14 |
| Growth Velocity Z Score From Pre-Treatment | -2.14 Z score STANDARD_DEVIATION 5.571 | -1.37 Z score STANDARD_DEVIATION 1.334 | -1.75 Z score STANDARD_DEVIATION 4.022 |
| Height-For-Age Z-Score | -2.05 Z score STANDARD_DEVIATION 0.868 | -2.32 Z score STANDARD_DEVIATION 1.167 | -2.17 Z score STANDARD_DEVIATION 1.018 |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference Domain | 49.9 T-score STANDARD_DEVIATION 12.05 | 53.1 T-score STANDARD_DEVIATION 10.95 | 51.3 T-score STANDARD_DEVIATION 11.54 |
| Percent of Predicted Normal in the 6MWT Total Distance | 76.20 perecent of predicted meters STANDARD_DEVIATION 14.838 | 62.13 perecent of predicted meters STANDARD_DEVIATION 18.629 | 70.17 perecent of predicted meters STANDARD_DEVIATION 17.771 |
| PROMIS Fatigue Domain | 47.0 T-score STANDARD_DEVIATION 13.7 | 48.8 T-score STANDARD_DEVIATION 9.6 | 47.8 T-score STANDARD_DEVIATION 11.98 |
| PROMIS Physical Function Mobility Domain | 45.5 T-score STANDARD_DEVIATION 9.86 | 45.2 T-score STANDARD_DEVIATION 9.05 | 45.3 T-score STANDARD_DEVIATION 9.39 |
| Race/Ethnicity, Customized Asian | 6 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Other (Not Specified) | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 25 Participants | 50 Participants |
| Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate(TmP/GFR) | 2.008 mg/dL STANDARD_DEVIATION 0.33 | 2.193 mg/dL STANDARD_DEVIATION 0.3733 | 2.091 mg/dL STANDARD_DEVIATION 0.3587 |
| Rickets Severity Score (RSS) Total Score | 3.19 score on a scale STANDARD_DEVIATION 1.141 | 3.17 score on a scale STANDARD_DEVIATION 0.975 | 3.18 score on a scale STANDARD_DEVIATION 1.057 |
| Serum 1,25(OH)D | 40.18 pg/mL STANDARD_DEVIATION 14.886 | 46.00 pg/mL STANDARD_DEVIATION 20.06 | 42.99 pg/mL STANDARD_DEVIATION 17.663 |
| Serum Alkaline Phosphatase (ALP) Concentration | 523.44 U/L STANDARD_DEVIATION 154.419 | 510.76 U/L STANDARD_DEVIATION 124.903 | 517.4 U/L STANDARD_DEVIATION 140.15 |
| Serum Phosphorus | 2.30 mg/dL STANDARD_DEVIATION 0.257 | 2.42 mg/dL STANDARD_DEVIATION 0.244 | 2.36 mg/dL STANDARD_DEVIATION 0.256 |
| Sex: Female, Male Female | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Male | 14 Participants | 13 Participants | 27 Participants |
| Six Minute Walk Test (6MWT) Total Distance | 450.50 meters STANDARD_DEVIATION 106.432 | 365.93 meters STANDARD_DEVIATION 118.083 | 414.26 meters STANDARD_DEVIATION 117.79 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 29 | 0 / 26 | 0 / 29 | 0 / 55 |
| other Total, other adverse events | 23 / 32 | 21 / 29 | 9 / 26 | 25 / 29 | 34 / 55 |
| serious Total, serious adverse events | 3 / 32 | 3 / 29 | 0 / 26 | 4 / 29 | 4 / 55 |
Outcome results
Primary
Radiographic Global Impression of Change (RGI-C) Global Score at Week 40
Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).
Time frame: Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Radiographic Global Impression of Change (RGI-C) Global Score at Week 40 | 0.77 score on a scale | Standard Error 0.107 |
| Burosumab | Radiographic Global Impression of Change (RGI-C) Global Score at Week 40 | 1.92 score on a scale | Standard Error 0.11 |
Comparison: Least squares (LS) mean, standard error (SE), confidence interval (CI), and 2-sided p value per ANCOVA model, which included RGI-C as the dependent variable, treatment group and baseline age stratification factor as independent variables and baseline RSS score as a continuous covariate.p-value: <0.000195% CI: [0.83, 1.45]ANCOVA
Secondary
Change From Baseline in Height-For-Age Z-Scores to Week 40
Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the Centers for Disease Control \[CDC\] growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.
Time frame: Baseline, Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in Height-For-Age Z-Scores to Week 40 | 0.03 Z score | Standard Error 0.031 |
| Burosumab | Change From Baseline in Height-For-Age Z-Scores to Week 40 | 0.16 Z score | Standard Error 0.052 |
Comparison: LS mean, SE, CI, and 2-sided p value per GEE model, which included change from baseline for recumbent length/standing height Z score as the dependent variable, treatment group, visit, interaction between treatment group by visit and baseline RSS stratification as factors, age and baseline recumbent length/standing height Z score as continuous covariates, with exchangeable covariance structure.p-value: 0.040895% CI: [0.01, 0.24]GEE model
Secondary
Change From Baseline in Height-For-Age Z-Scores to Week 64
Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.
Time frame: Baseline, Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in Height-For-Age Z-Scores to Week 64 | 0.02 Z score | Standard Error 0.035 |
| Burosumab | Change From Baseline in Height-For-Age Z-Scores to Week 64 | 0.17 Z score | Standard Error 0.066 |
Comparison: LS mean, SE, CI, and 2-sided p value per GEE model, which included change from baseline for recumbent length/standing height Z score as the dependent variable, treatment group, visit, interaction between treatment group by visit and baseline RSS stratification as factors, age and baseline recumbent length/standing height Z score as continuous covariates, with exchangeable covariance structure.p-value: 0.04995% CI: [0, 0.29]GEE model
Secondary
Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)
Time frame: Burosumab arm: Baseline, Week 1, 4, 8, 16, 24, 32, 40, 52, 64, 66, 68, 76, 88, 100, 112, 124, 140; Active Control arm: Baseline, Week 68, 76, 88, 100, 112, 124, 140
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab) | 1.05 mg/dL | Standard Deviation 0.31 |
| Burosumab | Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab) | 0.93 mg/dL | Standard Deviation 0.336 |
Secondary
Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64
The ANCOVA model includes change in serum phosphorus from baseline to mean post-baseline as the dependent variable, treatment group, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate.
Time frame: Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64 | 0.24 mg/dL | Standard Error 0.058 |
| Burosumab | Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64 | 0.98 mg/dL | Standard Error 0.061 |
p-value: <0.000195% CI: [0.58, 0.91]ANCOVA
Secondary
Change From Baseline in RSS Total Score at Week 40
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, lucency, separation, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees (the total score is the sum of the wrist and knee score). Higher scores indicate greater rickets severity.
Time frame: Baseline, Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline RSS Total Score assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in RSS Total Score at Week 40 | -0.71 score on a scale | Standard Error 0.138 |
| Burosumab | Change From Baseline in RSS Total Score at Week 40 | -2.04 score on a scale | Standard Error 0.145 |
p-value: <0.000195% CI: [-1.74, -0.94]ANCOVA
Secondary
Change From Baseline in RSS Total Score at Week 64
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.
Time frame: Baseline, Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline RSS Total Score assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in RSS Total Score at Week 64 | -1.01 score on a scale | Standard Error 0.151 |
| Burosumab | Change From Baseline in RSS Total Score at Week 64 | -2.23 score on a scale | Standard Error 0.117 |
p-value: <0.000195% CI: [-1.59, -0.83]GEE model
Secondary
Change From Baseline in the 6MWT Total Distance at Week 40
The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test.
Time frame: Baseline, Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40 in subjects ≥ 5 years who were able to complete the test.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in the 6MWT Total Distance at Week 40 | 3.65 meters | Standard Error 14.06 |
| Burosumab | Change From Baseline in the 6MWT Total Distance at Week 40 | 47.10 meters | Standard Error 15.768 |
Comparison: 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.051495% CI: [-0.26, 87.17]GEE model
Secondary
Change From Baseline in the 6MWT Total Distance at Week 64
The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test.
Time frame: Baseline, Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in the 6MWT Total Distance at Week 64 | 29.28 meters | Standard Error 16.834 |
| Burosumab | Change From Baseline in the 6MWT Total Distance at Week 64 | 74.83 meters | Standard Error 12.513 |
Comparison: 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.039995% CI: [2.09, 89.02]GEE model
Secondary
Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40
The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain.
Time frame: Baseline, Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | 0.02 units on a scale | Standard Error 0.323 |
| Burosumab | Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | 0.03 units on a scale | Standard Error 0.323 |
Comparison: GEE model includes change from baseline for FPS-R as the dependent variable, treatment group, visit, interaction between treatment group by visit and baseline RSS stratification as factors, baseline FPS-R as a covariate, with exchangeable covariance structure. The LS Mean, SE, 95% CI and 2-sided p-value are from the GEE model.p-value: 0.986295% CI: [-0.79, 0.8]GEE model
Secondary
Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64
The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain.
Time frame: Baseline, Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | 0.04 units on a scale | Standard Error 0.27 |
| Burosumab | Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | -0.01 units on a scale | Standard Error 0.234 |
Comparison: GEE model includes change from baseline for FPS-R as the dependent variable, treatment group, visit, interaction between treatment group by visit and baseline RSS stratification as factors, baseline FPS-R as a covariate, with exchangeable covariance structure. The LS Mean, SE, 95% CI and 2-sided p-value are from the GEE model.p-value: 0.878695% CI: [-0.58, 0.68]GEE model
Secondary
Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40
The PROMIS was developed by the National Institutes of Health and uses domain-specific measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue.
Time frame: Baseline, Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Pain Interference Domain Score | -0.29 T-score | Standard Error 1.539 |
| Active Control | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Physical Function Mobility Domain Score | 0.10 T-score | Standard Error 0.966 |
| Active Control | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Fatigue Domain Score | -1.05 T-score | Standard Error 1.754 |
| Burosumab | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Pain Interference Domain Score | -5.31 T-score | Standard Error 1.705 |
| Burosumab | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Physical Function Mobility Domain Score | 2.78 T-score | Standard Error 1.336 |
| Burosumab | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 | Fatigue Domain Score | -4.29 T-score | Standard Error 1.709 |
Comparison: Pain Interference Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.021295% CI: [-9.29, -0.75]GEE model
Comparison: Physical Function Mobility Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.100995% CI: [-0.52, 5.89]GEE model
Comparison: Fatigue Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.167695% CI: [-7.86, 1.37]GEE model
Secondary
Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64
The PROMIS was developed by the National Institutes of Health and uses domain-specific measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue.
Time frame: Baseline, Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Pain Interference Domain Score | -1.29 T-score | Standard Error 1.267 |
| Active Control | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Physical Function Mobility Domain Score | 0.92 T-score | Standard Error 0.962 |
| Active Control | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Fatigue Domain Score | -2.57 T-score | Standard Error 1.547 |
| Burosumab | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Pain Interference Domain Score | -3.55 T-score | Standard Error 1.873 |
| Burosumab | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Physical Function Mobility Domain Score | 2.82 T-score | Standard Error 1.648 |
| Burosumab | Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 | Fatigue Domain Score | -3.65 T-score | Standard Error 2.119 |
Comparison: Pain Interference Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.309195% CI: [-6.61, 2.09]GEE model
Comparison: Physical Function Mobility Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.314595% CI: [-1.8, 5.59]GEE model
Comparison: Fatigue Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.68195% CI: [-6.21, 4.06]GEE model
Secondary
Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64
The GEE model includes change from baseline for 1, 25-Dihydroxyvitamin D measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline 1, 25-Dihydroxyvitamin D measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.
Time frame: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 1 | 19.81 pg/mL | Standard Error 2.758 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 4 | 12.77 pg/mL | Standard Error 2.998 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 8 | 15.10 pg/mL | Standard Error 2.528 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 16 | 19.41 pg/mL | Standard Error 3.757 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 24 | 17.46 pg/mL | Standard Error 2.905 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 32 | 17.25 pg/mL | Standard Error 3.156 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 40 | 18.42 pg/mL | Standard Error 3.594 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 52 | 8.74 pg/mL | Standard Error 3.866 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 64 | 1.19 pg/mL | Standard Error 2.785 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 16 | 32.38 pg/mL | Standard Error 3.032 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 40 | 29.63 pg/mL | Standard Error 3.721 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 24 | 28.35 pg/mL | Standard Error 3.113 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 64 | 9.89 pg/mL | Standard Error 2.235 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 1 | 68.09 pg/mL | Standard Error 5.251 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 2 | 31.78 pg/mL | Standard Error 5.13 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 32 | 23.49 pg/mL | Standard Error 2.439 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 4 | 33.86 pg/mL | Standard Error 3.561 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 33 | 31.50 pg/mL | Standard Error 3.423 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 8 | 30.85 pg/mL | Standard Error 3.83 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 12 | 33.43 pg/mL | Standard Error 3.176 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 | Week 52 | 13.75 pg/mL | Standard Error 2.862 |
Comparison: Week 1p-value: <0.000195% CI: [36.53, 60.02]GEE model
Comparison: Week 4p-value: <0.000195% CI: [12.01, 30.16]GEE model
Comparison: Week 8p-value: 0.00195% CI: [6.35, 25.15]GEE model
Comparison: Week 16p-value: 0.007895% CI: [3.41, 22.53]GEE model
Comparison: Week 24p-value: 0.010195% CI: [2.59, 19.19]GEE model
Comparison: Week 32p-value: 0.116595% CI: [-1.55, 14.02]GEE model
Comparison: Week 40p-value: 0.031795% CI: [0.98, 21.44]GEE model
Comparison: Week 52p-value: 0.304495% CI: [-4.55, 14.56]GEE model
Comparison: Week 64p-value: 0.014595% CI: [1.72, 15.68]GEE model
Secondary
Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112
Time frame: Baseline, Weeks 68, 76, 88, 100, 112
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 76 | 19.05 pg/mL | Standard Deviation 22.612 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 100 | 33.57 pg/mL | Standard Deviation 16.591 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 88 | 24.58 pg/mL | Standard Deviation 17.787 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 112 | 29.94 pg/mL | Standard Deviation 15.402 |
| Active Control | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 68 | 22.12 pg/mL | Standard Deviation 23.95 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 112 | 31.05 pg/mL | Standard Deviation 33.729 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 68 | -9.80 pg/mL | — |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 76 | 12.80 pg/mL | Standard Deviation 20.093 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 88 | 11.76 pg/mL | Standard Deviation 22.874 |
| Burosumab | Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112 | Week 100 | 13.25 pg/mL | Standard Deviation 1.061 |
Secondary
Change From Baseline Over Time in Serum ALP, up to Week 64
The GEE model includes change from baseline for ALP measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline ALP measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.
Time frame: Baseline, Weeks 16, 24, 40, 52, 64
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 24 | -22.43 U/L | Standard Error 15.074 |
| Active Control | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 52 | -50.03 U/L | Standard Error 18.641 |
| Active Control | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 40 | -34.78 U/L | Standard Error 18.132 |
| Active Control | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 64 | -28.06 U/L | Standard Error 19.98 |
| Active Control | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 16 | -5.43 U/L | Standard Error 17.885 |
| Burosumab | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 64 | -174.62 U/L | Standard Error 13.427 |
| Burosumab | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 16 | -97.97 U/L | Standard Error 11.281 |
| Burosumab | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 24 | -108.00 U/L | Standard Error 16.225 |
| Burosumab | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 40 | -130.72 U/L | Standard Error 12.365 |
| Burosumab | Change From Baseline Over Time in Serum ALP, up to Week 64 | Week 52 | -161.31 U/L | Standard Error 11.674 |
Comparison: Week 16p-value: <0.000195% CI: [-131.4, -53.66]GEE model
Comparison: Week 24p-value: <0.000195% CI: [-126.37, -44.76]GEE model
Comparison: Week 40p-value: <0.000195% CI: [-136.05, -55.84]GEE model
Comparison: Week 52p-value: <0.000195% CI: [-152.08, -70.49]GEE model
Comparison: Week 64p-value: <0.000195% CI: [-191.61, -101.52]GEE model
Secondary
Change From Baseline Over Time in Serum ALP, Week 68 to 112
Time frame: Baseline, Weeks 68, 76, 88, 100, 112
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 76 | -106.73 U/L | Standard Deviation 73.316 |
| Active Control | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 100 | -83.14 U/L | Standard Deviation 104.675 |
| Active Control | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 88 | -146.56 U/L | Standard Deviation 73.12 |
| Active Control | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 112 | -104.80 U/L | Standard Deviation 80.35 |
| Active Control | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 68 | -82.73 U/L | Standard Deviation 83.683 |
| Burosumab | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 112 | -172.00 U/L | Standard Deviation 26.87 |
| Burosumab | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 68 | -184.00 U/L | — |
| Burosumab | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 76 | -166.73 U/L | Standard Deviation 87.7 |
| Burosumab | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 88 | -154.55 U/L | Standard Deviation 48.148 |
| Burosumab | Change From Baseline Over Time in Serum ALP, Week 68 to 112 | Week 100 | -184.00 U/L | Standard Deviation 48.083 |
Secondary
Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64
The GEE model includes change from baseline for serum phosphorous measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.
Time frame: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
Population: Pharmacodynamic (PD) Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with data at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 32 | 0.23 mg/dL | Standard Error 0.063 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 4 | 0.18 mg/dL | Standard Error 0.061 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 1 | 0.22 mg/dL | Standard Error 0.072 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 40 | 0.20 mg/dL | Standard Error 0.062 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 16 | 0.24 mg/dL | Standard Error 0.063 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 52 | 0.30 mg/dL | Standard Error 0.082 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 8 | 0.21 mg/dL | Standard Error 0.064 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 64 | 0.21 mg/dL | Standard Error 0.062 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 24 | 0.27 mg/dL | Standard Error 0.073 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 40 | 0.92 mg/dL | Standard Error 0.08 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 52 | 0.91 mg/dL | Standard Error 0.075 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 24 | 0.78 mg/dL | Standard Error 0.077 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 64 | 0.91 mg/dL | Standard Error 0.078 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 1 | 1.26 mg/dL | Standard Error 0.094 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 2 | 1.14 mg/dL | Standard Error 0.098 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 4 | 1.21 mg/dL | Standard Error 0.102 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 8 | 0.99 mg/dL | Standard Error 0.074 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 12 | 1.01 mg/dL | Standard Error 0.072 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 16 | 0.87 mg/dL | Standard Error 0.072 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 32 | 0.93 mg/dL | Standard Error 0.073 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 | Week 33 | 1.23 mg/dL | Standard Error 0.106 |
Comparison: Week 1p-value: <0.000195% CI: [0.81, 1.27]GEE model
Comparison: Week 4p-value: <0.000195% CI: [0.79, 1.27]GEE model
Comparison: Week 8p-value: <0.000195% CI: [0.58, 0.97]GEE model
Comparison: Week 16p-value: <0.000195% CI: [0.44, 0.81]GEE model
Comparison: Week 24p-value: <0.000195% CI: [0.3, 0.72]GEE model
Comparison: Week 32p-value: <0.000195% CI: [0.51, 0.89]GEE model
Comparison: Week 40p-value: <0.000195% CI: [0.51, 0.91]GEE model
Comparison: Week 52p-value: <0.000195% CI: [0.39, 0.82]GEE model
Comparison: Week 64p-value: <0.000195% CI: [0.49, 0.9]GEE model
Secondary
Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112
Time frame: Baseline, Weeks 66, 68, 76, 88, 100, 112
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 66 | 0.05 mg/dL | Standard Deviation 0.235 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 68 | 1.17 mg/dL | Standard Deviation 0.472 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 76 | 0.90 mg/dL | Standard Deviation 0.324 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 88 | 0.98 mg/dL | Standard Deviation 0.433 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 100 | 0.99 mg/dL | Standard Deviation 0.445 |
| Active Control | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 112 | 1.26 mg/dL | Standard Deviation 0.508 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 88 | 1.00 mg/dL | Standard Deviation 0.576 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 68 | 1.10 mg/dL | — |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 112 | 1.10 mg/dL | Standard Deviation 0.283 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 76 | 0.92 mg/dL | Standard Deviation 0.324 |
| Burosumab | Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112 | Week 100 | 1.00 mg/dL | Standard Deviation 0.424 |
Secondary
Change From Baseline Over Time in TmP/GFR, up to Week 64
Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR. The GEE model includes change from baseline for TmP/GFR measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline TmP/GFR measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.
Time frame: Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 4 | -0.17 mg/dL | Standard Error 0.065 |
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 8 | -0.20 mg/dL | Standard Error 0.057 |
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 16 | -0.15 mg/dL | Standard Error 0.085 |
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 24 | -0.12 mg/dL | Standard Error 0.072 |
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 32 | -0.10 mg/dL | Standard Error 0.062 |
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 40 | -0.15 mg/dL | Standard Error 0.053 |
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 52 | -0.12 mg/dL | Standard Error 0.069 |
| Active Control | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 64 | -0.09 mg/dL | Standard Error 0.07 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 64 | 1.16 mg/dL | Standard Error 0.127 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 4 | 1.48 mg/dL | Standard Error 0.173 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 32 | 1.14 mg/dL | Standard Error 0.115 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 8 | 1.22 mg/dL | Standard Error 0.101 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 52 | 1.13 mg/dL | Standard Error 0.124 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 16 | 1.00 mg/dL | Standard Error 0.139 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 40 | 1.20 mg/dL | Standard Error 0.113 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, up to Week 64 | Week 24 | 0.99 mg/dL | Standard Error 0.134 |
Comparison: Week 4p-value: <0.000195% CI: [1.28, 2.02]GEE model
Comparison: Week 8p-value: <0.000195% CI: [1.19, 1.64]GEE model
Comparison: Week 16p-value: <0.000195% CI: [0.84, 1.48]GEE model
Comparison: Week 24p-value: <0.000195% CI: [0.8, 1.41]GEE model
Comparison: Week 32p-value: <0.000195% CI: [0.98, 1.51]GEE model
Comparison: Week 40p-value: <0.000195% CI: [1.1, 1.6]GEE model
Comparison: Week 52p-value: <0.000195% CI: [0.97, 1.54]GEE model
Comparison: Week 64p-value: <0.000195% CI: [0.96, 1.54]GEE model
Secondary
Change From Baseline Over Time in TmP/GFR, Week 68 to 112
Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR.
Time frame: Baseline, Weeks 68, 76, 88, 112
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 88 | 1.33 mg/dL | Standard Deviation 0.48 |
| Active Control | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 68 | 1.61 mg/dL | Standard Deviation 0.705 |
| Active Control | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 112 | 1.56 mg/dL | Standard Deviation 0.233 |
| Active Control | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 76 | 1.18 mg/dL | Standard Deviation 0.758 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 112 | 1.32 mg/dL | Standard Deviation 0.233 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 68 | 1.65 mg/dL | — |
| Burosumab | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 88 | 0.95 mg/dL | Standard Deviation 0.62 |
| Burosumab | Change From Baseline Over Time in TmP/GFR, Week 68 to 112 | Week 76 | 0.59 mg/dL | Standard Deviation 0.429 |
Secondary
Change in Growth Velocity Z Score From Baseline to Week 40
A growth velocity Z score was calculated based on Tanner's standard. The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for participants who had data available from within 1.5 years prior to baseline. The Week 64 growth velocity was calculated using data between baseline and Week 64. The mid-point of the age interval was used to locate the closest reference age provided by Tanner's Standard. Children with a mid-point age under 2.25 years were excluded, because younger ages are not available in Tanner's standard. To smoothly transition from recumbent length to standing height, 0·8 cm was subtracted from recumbent length before pooling with standing height. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome.
Time frame: Baseline, Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with Baseline growth velocity.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change in Growth Velocity Z Score From Baseline to Week 40 | 0.73 Z score | Standard Error 0.339 |
| Burosumab | Change in Growth Velocity Z Score From Baseline to Week 40 | 1.76 Z score | Standard Error 0.337 |
Comparison: LS mean, SE, CI, and 2-sided p value per ANCOVA model, which included change from baseline for growth velocity Z score as the dependent variable, treatment group and baseline RSS total score stratification as factors, baseline Z score and age as continuous covariates.p-value: 0.038695% CI: [0.06, 1.99]ANCOVA
Secondary
Change in Growth Velocity Z Score From Baseline to Week 64
A growth velocity Z score was calculated based on Tanner's standard. The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for participants who had data available from within 1.5 years prior to baseline. The Week 64 growth velocity was calculated using data between baseline and Week 64. The mid-point of the age interval was used to locate the closest reference age provided by Tanner's Standard. Children with a mid-point age under 2.25 years were excluded, because younger ages are not available in Tanner's standard. To smoothly transition from recumbent length to standing height, 0·8 cm was subtracted from recumbent length before pooling with standing height. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome.
Time frame: Baseline, Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with Baseline growth velocity.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Change in Growth Velocity Z Score From Baseline to Week 64 | 0.41 Z score | Standard Error 0.265 |
| Burosumab | Change in Growth Velocity Z Score From Baseline to Week 64 | 1.53 Z score | Standard Error 0.264 |
Comparison: LS mean, SE, CI, and 2-sided p value per ANCOVA model, which included change from baseline for growth velocity Z score as the dependent variable, treatment group and baseline RSS total score stratification as factors, baseline Z score and age as continuous covariates.p-value: 0.004795% CI: [0.37, 1.88]ANCOVA
Secondary
Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)
Time frame: Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Control | Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL) | 75.0 percentage of participants |
| Burosumab | Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL) | 96.6 percentage of participants |
Secondary
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40
RGI-C responders are defined as participants with a mean RGI-C global score \>= +2.0. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).
Time frame: Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Control | Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40 | 6.3 percentage of participants |
| Burosumab | Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40 | 72.4 percentage of participants |
p-value: <0.000195% CI: [7.2, 211.7]Regression, Logistic
Secondary
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64
RGI-C responders are defined as participants with a mean RGI-C global score \>= +2.0. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).
Time frame: Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Control | Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64 | 18.8 percentage of participants |
| Burosumab | Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64 | 86.2 percentage of participants |
p-value: 0.000295% CI: [5.6, 206.3]generalized linear mixed model
Secondary
Percent Change From Baseline Over Time in Serum ALP, up to Week 112
Decreases indicate improvement.
Time frame: Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112
Population: PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 68 | -14.66 percent change | Standard Deviation 14.76 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 16 | 0.41 percent change | Standard Deviation 21.021 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 24 | -3.21 percent change | Standard Deviation 15.827 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 40 | -6.85 percent change | Standard Deviation 16.493 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 52 | -8.60 percent change | Standard Deviation 19.027 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 64 | -4.60 percent change | Standard Deviation 20.711 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 76 | -20.49 percent change | Standard Deviation 13.926 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 88 | -28.77 percent change | Standard Deviation 12.201 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 100 | -16.06 percent change | Standard Deviation 23.703 |
| Active Control | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 112 | -21.00 percent change | Standard Deviation 15.053 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 88 | -32.02 percent change | Standard Deviation 10.61 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 68 | -38.02 percent change | — |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 64 | -32.78 percent change | Standard Deviation 13.095 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 16 | -18.39 percent change | Standard Deviation 10.815 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 112 | -36.67 percent change | Standard Deviation 6.868 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 24 | -19.88 percent change | Standard Deviation 17.642 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 76 | -31.42 percent change | Standard Deviation 13.422 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 40 | -24.38 percent change | Standard Deviation 13.498 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 100 | -39.29 percent change | Standard Deviation 11.46 |
| Burosumab | Percent Change From Baseline Over Time in Serum ALP, up to Week 112 | Week 52 | -30.60 percent change | Standard Deviation 11.852 |
Secondary
Percent of Predicted Normal in the 6MWT Total Distance at Week 40
The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test, and the percent predicted distance based on normative data for age and gender was estimated.
Time frame: Baseline, Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Percent of Predicted Normal in the 6MWT Total Distance at Week 40 | -1.14 percent of predicted meters | Standard Error 2.224 |
| Burosumab | Percent of Predicted Normal in the 6MWT Total Distance at Week 40 | 5.59 percent of predicted meters | Standard Error 2.633 |
Comparison: 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.063395% CI: [-0.37, 13.82]GEE model
Secondary
Percent of Predicted Normal in the 6MWT Total Distance at Week 64
The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test, and the percent predicted distance based on normative data for age and gender was estimated.
Time frame: Baseline, Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | Percent of Predicted Normal in the 6MWT Total Distance at Week 64 | 1.88 percent of predicted meters | Standard Error 2.789 |
| Burosumab | Percent of Predicted Normal in the 6MWT Total Distance at Week 64 | 9.15 percent of predicted meters | Standard Error 2.056 |
Comparison: 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.p-value: 0.049695% CI: [0.01, 14.52]GEE model
Secondary
RGI-C Global Score at Week 64
Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).
Time frame: Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | RGI-C Global Score at Week 64 | 1.03 score on a scale | Standard Error 0.136 |
| Burosumab | RGI-C Global Score at Week 64 | 2.06 score on a scale | Standard Error 0.072 |
Comparison: Per generalized estimating equation (GEE) model, which included RGI-C as the dependent variable, treatment, visit, treatment by visit interaction and baseline age stratification factor as factors, baseline RSS score as a continuous covariate, with exchangeable covariate structure.p-value: <0.000195% CI: [0.72, 1.33]GEE model
Secondary
RGI-C Long Leg Score at Week 40
Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening).
Time frame: Week 40
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | RGI-C Long Leg Score at Week 40 | 0.22 score on a scale | Standard Error 0.08 |
| Burosumab | RGI-C Long Leg Score at Week 40 | 0.62 score on a scale | Standard Error 0.153 |
p-value: 0.016295% CI: [0.07, 0.72]GEE model
Secondary
RGI-C Long Leg Score at Week 64
Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening).
Time frame: Week 64
Population: Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Control | RGI-C Long Leg Score at Week 64 | 0.29 score on a scale | Standard Error 0.119 |
| Burosumab | RGI-C Long Leg Score at Week 64 | 1.25 score on a scale | Standard Error 0.17 |
p-value: <0.000195% CI: [0.57, 1.37]GEE model