Epidermal Nevus Syndrome (ENS), Tumor Induced Osteomalacia (TIO)
Conditions
Keywords
TIO, ENS, FGF23, KRN23
Brief summary
The primary objectives of this study are to evaluate the effect of burosumab treatment on: * Increasing serum phosphorus levels in adults with TIO or ENS-associated osteomalacia * Improvement in TIO/ENS-associated osteomalacia as determined by osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), osteoid volume/bone volume (OV/BV) and mineralization lag time (MLt).
Interventions
BIOLOGICALBurosumab
Solution for subcutaneous injection
Sponsors
Kyowa Kirin, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have a clinical diagnosis of TIO/ENS-associated osteomalacia based on evidence of excessive fibroblast growth factor 23 (FGF23) that was not amenable to cure by surgical excision of the underlying tumor/lesion (documented by Investigator). 2. Be ≥ 18 years of age 3. Have a fasting serum phosphorus level \< 2.5 mg/dL 4. Have an FGF23 level ≥ 100 pg/mL by Kainos assay 5. Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) \< 2.5 mg/dL 6. Have an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using Cockcroft-Gault formula). Subjects with eGFR ≥ 30 but \< 60 mL/min will be considered eligible as long as in the opinion of the investigator the decline in renal function is not related to nephrocalcinosis. 7. Have a corrected serum calcium level \< 10.8 mg/dL 8. Females of child-bearing potential must have a negative urine pregnancy test at Screening and Baseline and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have not experienced menarche, are post-menopausal (defined as having no menses for at least 12 months without an alternative medical cause) or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 9. Be willing to use 2 forms of effective methods of contraception while participating in the study (sexually active subjects) and for 12 weeks after last dose of study drug. 10. Be willing to provide access to prior medical records to determine eligibility including imaging, biochemical, and diagnostic, medical, and surgical history data 11. Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures 12. Be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments (in the opinion of the investigator)
Exclusion criteria
1. Have a prior diagnosis of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C 2. Have a history of recurrent infection, a predisposition to infection, or a known immunodeficiency 3. Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or partner) at any time during the study 4. Have participated in an investigational drug or device trial within 30 days prior to Screening or are currently enrolled in another study of an investigational product or device 5. Have used a therapeutic monoclonal antibody (mAb), including KRN23, within 90 days prior to Screening or have a history of allergic or anaphylactic reactions to any mAb 6. Have or a have a history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects 7. Have used a pharmacologic vitamin D metabolite or its analog (e.g., calcitriol, doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) within 2 weeks prior to Screening or during the study 8. Have used medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening 9. Have a history of malignancy within 5 years of study entry with the exception of phosphaturic mesenchymal tumors (PMTs) of the mixed connective tissue type or non-melanoma skin cancers such as basal cell skin cancer 10. Have donated blood or blood products within 60 days prior to Screening 11. Have a history of allergic reaction to or have shown adverse reactions to a tetracycline (e.g., tetracycline hydrochloride \[HCl\] and demeclocycline), benzodiazepines, fentanyl or lidocaine 12. Have any condition, which in the opinion of the investigator and sponsor, could present a concern for either subject safety or difficulty with data interpretation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24 | Mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22 [there was no study visit at Week 18]) | The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL \[0.81 mmol/L\]) at the mid-point of the dose interval (2 weeks after dosing), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22). |
| Change From Baseline to Week 48 in Osteoid Thickness | Baseline, Week 48 | Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid thickness is the mean thickness of osteoid seams. |
| Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS) | Baseline, Week 48 | Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid surface/bone surface is expressed as the percentage of bone surface covered in osteoid. |
| Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV) | Baseline, Week 48 | Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid volume/bone volume is expressed as the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid). |
| Change From Baseline to Week 48 in Mineralization Lag Time (MLt) | Baseline, Week 48 | Mineralization lag time is a dynamic modeling parameter representing the mean time interval between the formation of osteoid and its subsequent mineralization which can be measured using histomorphometry with double tetracycline labeling. Mlt was calculated by dividing the osteoid width by the mineralizing apposition rate (MAR; the average rate at which new bone mineral is being added on any actively forming surface). If Mlt could not be calculated directly due to low tetracycline uptake, Mlt was imputed according to the following: Mlt = O.Th/(MAR\*MS/OS), where O.Th = osteoid thickness, MAR is imputed as 0.3 μm/day, MS/OS=mineralizing surface/osteoid surface, each measured at the same visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The mental health (MH) domain includes 5 questions that assess general mental health (psychological distress and well-being). The MH domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The social functioning (SF) domain includes 2 questions that assess limitations in social activities because of physical health or emotional problems. The SF domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The role-emotional (RE) domain includes 3 questions that assess limitations in usual role activities because of emotional problems. The RE domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24 | End of each dose interval from Baseline to Week 24 (Weeks 4, 8, 12, 16, 20, and 24) | The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (2.5 mg/dL \[0.81 mmol/L\]) at the end of the dose interval (4 weeks post-dose, prior to the next dose), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24). |
| Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 | Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22) | Mean change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22). |
| Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 | Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22) | Mean percent change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22). |
| Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 | Baseline and Weeks 4, 8, 12, 16, 20, and 24 | Mean change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24). |
| Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 | Baseline and Weeks 4, 8, 12, 16, 20, and 24 | Mean percent change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24). |
| Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24 | Pre-dose on Day 1 and at Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 21, 22, and 24 | Serum phosphorus level versus time AUC was calculated using the trapezoidal rule. Time-adjusted AUC was calculated by dividing the AUC by duration of time included in AUC calculation. |
| Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares (LS) means and standard errors (SE) were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 1,25(OH)2D, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Total FGF23 included free FGF23 and FGF23 bound to burosumab. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline total FGF23, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline free FGF23, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 24-hour Urinary Phosphorus | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 24-hour urinary phosphorus, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Tubular reabsorption of phosphate (TRP) is the fraction of filtered phosphorus that is reabsorbed by renal tubules. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline TRP, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | TmP/GFR measures renal phosphate reabsorption (the primary mechanism by which FGF23 regulates phosphate homeostasis) by comparing the fractional absorption of phosphate relative to the estimated rate of glomerular filtration. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline TmP/GFR, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | FEP is the percentage of phosphorus filtered by the kidney that is excreted into urine, calculated as 100% \* (2-hour urine phosphorus\*serum creatinine)/(2-hour urine creatinine \* serum phosphorus). Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline FEP, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline ALP, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BALP, with compound symmetry covariance structure. |
| Percent Change From Baseline Over Time in BALP | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BALP, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline CTx, with compound symmetry covariance structure. |
| Percent Change From Baseline Over Time in CTx | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline CTx, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline P1NP, with compound symmetry covariance structure. |
| Percent Change From Baseline Over Time in P1NP | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline P1NP, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Osteocalcin | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline osteocalcin, with compound symmetry covariance structure. |
| Percent Change From Baseline Over Time in Osteocalcin | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline osteocalcin, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements | Baseline and Weeks 24 and 48 | To assess muscle strength, hand-held dynamometry was conducted using a standardized technique. Bilateral strength (defined as the average of the left and the right scores, measured in kilograms) of the elbow flexors and extensors was measured by the maximum voluntary isometric contraction against a dynamometer. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline strength measurements, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements | Baseline and Weeks 24 and 48 | To assess muscle strength, hand-held dynamometry was conducted using a standardized technique. Bilateral strength (defined as the average of the left and the right scores, measured in kilograms) of the knee flexors and extensors was measured by the maximum voluntary isometric contraction against a dynamometer. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline strength measurements, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Sit-to-Stand (STS) Test | Baseline and Weeks 24 and 48 | The STS test measures lower extremity strength and mobility as a participant moves repeatedly from a seated position to standing. This study used a modified STS test that allowed participants to use the arms of the chair to help them stand and sit if necessary. The number of sit-to-stand repetitions performed in a 30-second period was recorded. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Weighted Arm Lift (WAL) Test | Baseline and Weeks 24 and 48 | The Weighted arm lift (WAL) test assesses upper extremity strength, mobility and reaching ability. The test was administered bilaterally to determine the number of times the participant could raise a 1 kg weight above the head in a 30-second period. The number of repetitions completed with each arm was recorded. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline WAL measurements, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Six-Minute Walk Test (6MWT) | Baseline and Weeks 24 and 48 | The 6MWT is a commonly used measure of mobility and was conducted in accordance with general principles set forth in the American Thoracic Society guidelines (ATS 2002). Participants were instructed to walk the length of a pre-measured course for 6 consecutive minutes (assistive devices could be used). The total distance walked at the end of 6 minutes was recorded in meters. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 6MWT measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours. Worst pain is defined as the answer to Question 3, in which participants rated their pain at its worst in the last 24 hours on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours. Pain severity is defined as the average of 4 questions (Questions 3 through 6) assessing worst pain, least pain, average pain, and pain right now, rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). Mild pain is defined as a score of 1 to 4, moderate pain is defined as a score of 5 to 6, and severe pain is defined as a score of 7 to 10. A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours. Pain interference is defined as the average of 7 questions (9A through 9G) regarding the extent to which pain interfered with daily activities, including general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life in the last 24 hours, rated on a scale from 0 (does not interfere) to 10 (completely interferes). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. Worst fatigue is defined as the answer to Question 3 in which participants rated their fatigue at its worst in the last 24 hours on a scale from 0 (no fatigue) to 10 (as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. Fatigue severity is defined as the average of 3 questions (Questions 1 through 3) assessing fatigue right now, usual level of fatigue, and worst fatigue, rated on a scale from 0 (no fatigue) to 10 (as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. The fatigue interference score is defined as the average of 6 questions (Questions 4A through 4F) regarding the extent to which fatigue interfered with daily activities, including general activity, mood, walking ability, work, relations with others, and enjoyment of life in the last 24 hours, rated on a scale from 0 (does not interfere) to 10 (completely interferes). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. The first 3 questions measure fatigue severity and the next 6 questions assess the impact of fatigue on daily activities. The global fatigue score is defined as the average of all 9 questions on the BFI including severity and interference, and ranges from from 0 to 10, where higher scores correspond to greater levels of fatigue. A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary score (PCS) is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance struct |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical functioning (PF) domain includes 10 questions that assess limitations in physical activities because of health problems. The PF domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The role-physical (RP) domain includes 4 questions that assess limitations in usual role activities because of physical health problems. The RP domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The bodily pain (BP) domain includes 2 questions that assess pain level and impact of pain on normal work. The BP domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The general health perceptions (GH) domain includes 5 questions that assess participants' perception of their own general health. The GH domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The mental component summary score (MCS) is a weighted combination of the 8 subscales with positive weighting for vitality, social function, role limitations due to emotional problems, and mental health. The MCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
| Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240 | The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The vitality (VT) domain includes 4 questions that assess energy levels and fatigue. The VT domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Anti-burosumab Antibodies | From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days. | — |
| Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days. | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 8 centers in the United States, and enrolled adults with tumor-induced osteomalacia (TIO), epidermal nevus syndrome (ENS)-associated osteomalacia, or x-linked hypophosphatemia (XLH).
Participants by arm
| Arm | Count |
|---|---|
| Burosumab Participants received burosumab at a starting dose of 0.3 mg/kg administered subcutaneously (SC) every 4 weeks (Q4W). Doses may have been titrated up to a maximum of 2.0 mg/kg every 2 weeks (Q2W) in order to achieve fasting peak serum phosphorus levels within the target range of 2.5 to 4.0 mg/dL. | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Lack of Response to Bruosumab | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Sponsor Decision | 3 |
| Overall Study | Unable to Return Due to Corona Virus Pandemic | 1 |
Baseline characteristics
| Characteristic | Burosumab |
|---|---|
| Age, Continuous | 53.1 years STANDARD_DEVIATION 13.86 |
| Diagnosis Epidermal nevus syndrome-associated osteomalacia | 1 Participants |
| Diagnosis Tumor-Induced osteomalacia (TIO) | 14 Participants |
| Diagnosis X-linked hypophosphatemia (XLH) | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Mineralization Lag Time (Mlt) | 1597.73 days STANDARD_DEVIATION 1326.832 |
| Osteoid Surface/Bone Surface (OS/BS) | 56.82 percentage of bone surface STANDARD_DEVIATION 31.003 |
| Osteoid Thickness (O.Th) | 16.45 μm STANDARD_DEVIATION 12.044 |
| Osteoid Volume/Bone Volume (OB/BV) | 17.61 percentage of bone volume STANDARD_DEVIATION 19.485 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized White | 15 Participants |
| Serum Phosphorus | 1.60 mg/dL STANDARD_DEVIATION 0.474 |
| Serum Total Fibroblast Growth Factor 23 (FGF23) | 770.06 pg/mL STANDARD_DEVIATION 797.654 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 14 | 0 / 3 |
| other Total, other adverse events | 14 / 14 | 3 / 3 |
| serious Total, serious adverse events | 8 / 14 | 0 / 3 |
Outcome results
Primary
Change From Baseline to Week 48 in Mineralization Lag Time (MLt)
Mineralization lag time is a dynamic modeling parameter representing the mean time interval between the formation of osteoid and its subsequent mineralization which can be measured using histomorphometry with double tetracycline labeling. Mlt was calculated by dividing the osteoid width by the mineralizing apposition rate (MAR; the average rate at which new bone mineral is being added on any actively forming surface). If Mlt could not be calculated directly due to low tetracycline uptake, Mlt was imputed according to the following: Mlt = O.Th/(MAR\*MS/OS), where O.Th = osteoid thickness, MAR is imputed as 0.3 μm/day, MS/OS=mineralizing surface/osteoid surface, each measured at the same visit.
Time frame: Baseline, Week 48
Population: TIO biopsy analysis set for whom Mlt could be calculated or imputed
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Burosumab | Change From Baseline to Week 48 in Mineralization Lag Time (MLt) | -565.20 days |
Comparison: The null hypothesis that the mean change from Baseline to Week 48 in Mlt is zero was tested using a t-test.p-value: 0.4077t-test
Primary
Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS)
Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid surface/bone surface is expressed as the percentage of bone surface covered in osteoid.
Time frame: Baseline, Week 48
Population: TIO biopsy analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Burosumab | Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS) | -0.18 percentage of bone surface |
Comparison: The null hypothesis that the mean change from Baseline to Week 48 in OS/BS is zero was tested using a t-test.p-value: 0.977t-test
Primary
Change From Baseline to Week 48 in Osteoid Thickness
Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid thickness is the mean thickness of osteoid seams.
Time frame: Baseline, Week 48
Population: TIO bone biopsy analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Burosumab | Change From Baseline to Week 48 in Osteoid Thickness | -5.12 µm |
Comparison: The null hypothesis that the mean change from Baseline to Week 48 in osteoid thickness is zero was tested using a t-test.p-value: 0.0428t-test
Primary
Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV)
Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid volume/bone volume is expressed as the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).
Time frame: Baseline, Week 48
Population: TIO bone biopsy analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Burosumab | Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV) | -5.47 percentage of bone volume |
Comparison: The null hypothesis that the mean change from Baseline to Week 48 in OV/BV is zero was tested using a t-test.p-value: 0.0858t-test
Primary
Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24
The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL \[0.81 mmol/L\]) at the mid-point of the dose interval (2 weeks after dosing), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).
Time frame: Mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22 [there was no study visit at Week 18])
Population: TIO analysis set: includes participants with TIO who received at least 1 dose of burosumab during the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Burosumab | Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24 | 50.0 percentage of participants |
Secondary
Change From Baseline Over Time in 24-hour Urinary Phosphorus
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 24-hour urinary phosphorus, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 24 | -3.66 mg/dL | Standard Error 8.28 |
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 48 | 3.59 mg/dL | Standard Error 6.73 |
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 96 | 3.22 mg/dL | Standard Error 6.4 |
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 144 | 3.25 mg/dL | Standard Error 6.971 |
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 168 | 4.98 mg/dL | Standard Error 8.18 |
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 192 | 8.31 mg/dL | Standard Error 4.54 |
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 216 | 13.93 mg/dL | Standard Error 14.3 |
| Burosumab | Change From Baseline Over Time in 24-hour Urinary Phosphorus | Week 240 | 13.11 mg/dL | Standard Error 9.35 |
Comparison: Week 216p-value: 0.33GEE model
Comparison: Week 240p-value: 0.161GEE model
Comparison: Week 24p-value: 0.659GEE model
Comparison: Week 48p-value: 0.752GEE model
Comparison: Week 96p-value: 0.594GEE model
Comparison: Week 144p-value: 0.614GEE model
Comparison: Week 168p-value: 0.542GEE model
Comparison: Week 192p-value: 0.067GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The bodily pain (BP) domain includes 2 questions that assess pain level and impact of pain on normal work. The BP domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 24 | 1.61 score on a scale | Standard Error 1.65 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 48 | 3.61 score on a scale | Standard Error 1.48 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 96 | 2.52 score on a scale | Standard Error 1.08 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 144 | 5.40 score on a scale | Standard Error 1.9 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 168 | 5.01 score on a scale | Standard Error 2.16 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 192 | 4.92 score on a scale | Standard Error 2.81 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 216 | 6.64 score on a scale | Standard Error 1.88 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score | Week 240 | 6.59 score on a scale | Standard Error 2.2 |
Comparison: Week 24p-value: 0.328GEE model
Comparison: Week 48p-value: 0.015GEE model
Comparison: Week 96p-value: 0.02GEE model
Comparison: Week 144p-value: 0.004GEE model
Comparison: Week 168p-value: 0.021GEE model
Comparison: Week 192p-value: 0.08GEE model
Comparison: Week 216p-value: <0.001GEE model
Comparison: Week 240p-value: 0.003GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The general health perceptions (GH) domain includes 5 questions that assess participants' perception of their own general health. The GH domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 24 | 2.38 score on a scale | Standard Error 1.88 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 48 | 6.09 score on a scale | Standard Error 2.28 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 96 | 1.03 score on a scale | Standard Error 1.96 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 144 | 3.12 score on a scale | Standard Error 2.64 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 168 | -0.32 score on a scale | Standard Error 2.51 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 192 | -1.60 score on a scale | Standard Error 2.94 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 216 | -1.51 score on a scale | Standard Error 2.05 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score | Week 240 | 1.81 score on a scale | Standard Error 3.3 |
Comparison: Week 24p-value: 0.207GEE model
Comparison: Week 48p-value: 0.008GEE model
Comparison: Week 96p-value: 0.598GEE model
Comparison: Week 144p-value: 0.237GEE model
Comparison: Week 168p-value: 0.899GEE model
Comparison: Week 192p-value: 0.585GEE model
Comparison: Week 216p-value: 0.461GEE model
Comparison: Week 240p-value: 0.583GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The mental component summary score (MCS) is a weighted combination of the 8 subscales with positive weighting for vitality, social function, role limitations due to emotional problems, and mental health. The MCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 24 | 1.07 score on a scale | Standard Error 2.38 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 48 | 1.37 score on a scale | Standard Error 2.47 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 96 | 3.91 score on a scale | Standard Error 2.53 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 144 | -0.85 score on a scale | Standard Error 2.29 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 168 | 2.05 score on a scale | Standard Error 1.81 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 192 | 0.55 score on a scale | Standard Error 2.95 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 216 | 0.51 score on a scale | Standard Error 2.67 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score | Week 240 | 5.13 score on a scale | Standard Error 3.59 |
Comparison: Week 24p-value: 0.654GEE model
Comparison: Week 48p-value: 0.579GEE model
Comparison: Week 96p-value: 0.123GEE model
Comparison: Week 144p-value: 0.712GEE model
Comparison: Week 168p-value: 0.258GEE model
Comparison: Week 192p-value: 0.851GEE model
Comparison: Week 216p-value: 0.849GEE model
Comparison: Week 240p-value: 0.153GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The mental health (MH) domain includes 5 questions that assess general mental health (psychological distress and well-being). The MH domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 24 | -0.46 score on a scale | Standard Error 2.54 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 48 | -0.32 score on a scale | Standard Error 2.48 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 96 | -0.58 score on a scale | Standard Error 2.12 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 144 | -0.17 score on a scale | Standard Error 1.97 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 168 | -0.97 score on a scale | Standard Error 1.61 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 192 | -1.24 score on a scale | Standard Error 2.23 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 216 | -2.11 score on a scale | Standard Error 2.87 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score | Week 240 | 3.50 score on a scale | Standard Error 3.1 |
Comparison: Week 24p-value: 0.856GEE model
Comparison: Week 48p-value: 0.898GEE model
Comparison: Week 96p-value: 0.785GEE model
Comparison: Week 144p-value: 0.932GEE model
Comparison: Week 168p-value: 0.545GEE model
Comparison: Week 192p-value: 0.58GEE model
Comparison: Week 216p-value: 0.462GEE model
Comparison: Week 240p-value: 0.26GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary score (PCS) is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance struct
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 24 | 3.71 score on a scale | Standard Error 1.42 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 48 | 5.43 score on a scale | Standard Error 2.33 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 96 | 2.75 score on a scale | Standard Error 1.37 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 144 | 7.98 score on a scale | Standard Error 2.4 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 168 | 5.20 score on a scale | Standard Error 2.14 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 192 | 3.82 score on a scale | Standard Error 2.49 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 216 | 6.17 score on a scale | Standard Error 2.17 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score | Week 240 | 5.82 score on a scale | Standard Error 2.45 |
Comparison: Week 24p-value: 0.009GEE model
Comparison: Week 48p-value: 0.02GEE model
Comparison: Week 96p-value: 0.044GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: 0.015GEE model
Comparison: Week 192p-value: 0.125GEE model
Comparison: Week 216p-value: 0.004GEE model
Comparison: Week 240p-value: 0.018GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical functioning (PF) domain includes 10 questions that assess limitations in physical activities because of health problems. The PF domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 24 | 2.29 score on a scale | Standard Error 1.58 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 48 | 2.63 score on a scale | Standard Error 2.51 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 96 | 3.77 score on a scale | Standard Error 1.58 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 144 | 7.89 score on a scale | Standard Error 2 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 168 | 5.50 score on a scale | Standard Error 2.24 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 192 | 3.02 score on a scale | Standard Error 2.04 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 216 | 6.75 score on a scale | Standard Error 1.96 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score | Week 240 | 4.56 score on a scale | Standard Error 3.11 |
Comparison: Week 24p-value: 0.148GEE model
Comparison: Week 48p-value: 0.295GEE model
Comparison: Week 96p-value: 0.005GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: 0.014GEE model
Comparison: Week 192p-value: 0.14GEE model
Comparison: Week 216p-value: <0.001GEE model
Comparison: Week 240p-value: 0.142GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The role-emotional (RE) domain includes 3 questions that assess limitations in usual role activities because of emotional problems. The RE domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 24 | 1.52 score on a scale | Standard Error 1.98 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 48 | 1.13 score on a scale | Standard Error 2.72 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 96 | 6.73 score on a scale | Standard Error 3.03 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 144 | 2.10 score on a scale | Standard Error 2.6 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 168 | 4.90 score on a scale | Standard Error 2.22 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 192 | 3.51 score on a scale | Standard Error 3.47 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 216 | 3.56 score on a scale | Standard Error 3.08 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score | Week 240 | 6.04 score on a scale | Standard Error 3.69 |
Comparison: Week 24p-value: 0.442GEE model
Comparison: Week 48p-value: 0.677GEE model
Comparison: Week 96p-value: 0.027GEE model
Comparison: Week 144p-value: 0.42GEE model
Comparison: Week 168p-value: 0.027GEE model
Comparison: Week 192p-value: 0.312GEE model
Comparison: Week 216p-value: 0.249GEE model
Comparison: Week 240p-value: 0.102GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The role-physical (RP) domain includes 4 questions that assess limitations in usual role activities because of physical health problems. The RP domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 24 | 4.85 score on a scale | Standard Error 1.74 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 48 | 5.00 score on a scale | Standard Error 2.83 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 96 | 3.25 score on a scale | Standard Error 1.63 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 144 | 5.53 score on a scale | Standard Error 2.81 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 168 | 5.70 score on a scale | Standard Error 1.93 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 192 | 5.03 score on a scale | Standard Error 2.8 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 216 | 4.82 score on a scale | Standard Error 3.01 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score | Week 240 | 8.99 score on a scale | Standard Error 3.28 |
Comparison: Week 24p-value: 0.005GEE model
Comparison: Week 48p-value: 0.077GEE model
Comparison: Week 96p-value: 0.046GEE model
Comparison: Week 144p-value: 0.049GEE model
Comparison: Week 168p-value: 0.003GEE model
Comparison: Week 192p-value: 0.073GEE model
Comparison: Week 216p-value: 0.109GEE model
Comparison: Week 240p-value: 0.006GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The social functioning (SF) domain includes 2 questions that assess limitations in social activities because of physical health or emotional problems. The SF domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 24 | 2.02 score on a scale | Standard Error 2.24 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 48 | 5.54 score on a scale | Standard Error 2.48 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 96 | 4.63 score on a scale | Standard Error 1.34 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 144 | 3.22 score on a scale | Standard Error 2.71 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 168 | 5.34 score on a scale | Standard Error 2.06 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 192 | 2.84 score on a scale | Standard Error 2.62 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 216 | 4.15 score on a scale | Standard Error 2.08 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score | Week 240 | 6.30 score on a scale | Standard Error 2.98 |
Comparison: Week 24p-value: 0.369GEE model
Comparison: Week 48p-value: 0.026GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: 0.235GEE model
Comparison: Week 168p-value: 0.009GEE model
Comparison: Week 192p-value: 0.278GEE model
Comparison: Week 216p-value: 0.046GEE model
Comparison: Week 240p-value: 0.035GEE model
Secondary
Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score
The SF-36 v2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The vitality (VT) domain includes 4 questions that assess energy levels and fatigue. The VT domain score was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. LS means and SEs were estimated from a GEE model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline SF-36, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 24 | 5.98 score on a scale | Standard Error 1.96 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 48 | 5.27 score on a scale | Standard Error 2.42 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 96 | 6.71 score on a scale | Standard Error 2.64 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 144 | 3.05 score on a scale | Standard Error 2.3 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 168 | 6.04 score on a scale | Standard Error 2.74 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 192 | 2.78 score on a scale | Standard Error 2.85 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 216 | 6.79 score on a scale | Standard Error 3.77 |
| Burosumab | Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score | Week 240 | 8.06 score on a scale | Standard Error 4.03 |
Comparison: Week 24p-value: 0.002GEE model
Comparison: Week 48p-value: 0.03GEE model
Comparison: Week 96p-value: 0.011GEE model
Comparison: Week 144p-value: 0.186GEE model
Comparison: Week 168p-value: 0.027GEE model
Comparison: Week 192p-value: 0.33GEE model
Comparison: Week 216p-value: 0.072GEE model
Comparison: Week 240p-value: 0.045GEE model
Secondary
Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP)
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BALP, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 24 | -1.13 μg/L | Standard Error 4.87 |
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 48 | -9.65 μg/L | Standard Error 4.74 |
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 96 | -15.89 μg/L | Standard Error 4.27 |
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 144 | -19.81 μg/L | Standard Error 4.42 |
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 168 | -22.05 μg/L | Standard Error 4.52 |
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 192 | -21.54 μg/L | Standard Error 4.87 |
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 216 | -15.50 μg/L | Standard Error 11.39 |
| Burosumab | Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) | Week 240 | -21.58 μg/L | Standard Error 6.17 |
Comparison: Week 24p-value: 0.817GEE model
Comparison: Week 48p-value: 0.042GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: 0.174GEE model
Comparison: Week 240p-value: <0.001GEE model
Secondary
Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score
The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. The fatigue interference score is defined as the average of 6 questions (Questions 4A through 4F) regarding the extent to which fatigue interfered with daily activities, including general activity, mood, walking ability, work, relations with others, and enjoyment of life in the last 24 hours, rated on a scale from 0 (does not interfere) to 10 (completely interferes). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 24 | -1.57 score on a scale | Standard Error 0.65 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 48 | -1.88 score on a scale | Standard Error 0.66 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 96 | -1.98 score on a scale | Standard Error 0.47 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 144 | -1.67 score on a scale | Standard Error 0.44 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 168 | -2.20 score on a scale | Standard Error 0.38 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 192 | -1.24 score on a scale | Standard Error 0.59 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 216 | -2.72 score on a scale | Standard Error 1.02 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score | Week 240 | -3.00 score on a scale | Standard Error 1.14 |
Comparison: Week 24p-value: 0.016GEE model
Comparison: Week 48p-value: 0.004GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: 0.036GEE model
Comparison: Week 216p-value: 0.008GEE model
Comparison: Week 240p-value: 0.008GEE model
Secondary
Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score
The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. Fatigue severity is defined as the average of 3 questions (Questions 1 through 3) assessing fatigue right now, usual level of fatigue, and worst fatigue, rated on a scale from 0 (no fatigue) to 10 (as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 24 | -1.47 score on a scale | Standard Error 0.53 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 48 | -1.31 score on a scale | Standard Error 0.56 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 96 | -1.58 score on a scale | Standard Error 0.43 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 144 | -1.44 score on a scale | Standard Error 0.53 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 168 | -2.34 score on a scale | Standard Error 0.43 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 192 | -1.62 score on a scale | Standard Error 0.43 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 216 | -2.62 score on a scale | Standard Error 0.85 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score | Week 240 | -2.57 score on a scale | Standard Error 0.81 |
Comparison: Week 24p-value: 0.005GEE model
Comparison: Week 48p-value: 0.019GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: 0.006GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: 0.002GEE model
Comparison: Week 240p-value: 0.002GEE model
Secondary
Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score
The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. The first 3 questions measure fatigue severity and the next 6 questions assess the impact of fatigue on daily activities. The global fatigue score is defined as the average of all 9 questions on the BFI including severity and interference, and ranges from from 0 to 10, where higher scores correspond to greater levels of fatigue. A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 216 | -2.66 score on a scale | Standard Error 0.95 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 240 | -2.83 score on a scale | Standard Error 1.02 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 24 | -1.54 score on a scale | Standard Error 0.56 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 48 | -1.66 score on a scale | Standard Error 0.56 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 96 | -1.83 score on a scale | Standard Error 0.44 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 144 | -1.58 score on a scale | Standard Error 0.44 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 168 | -2.23 score on a scale | Standard Error 0.37 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score | Week 192 | -1.34 score on a scale | Standard Error 0.5 |
Comparison: Week 24p-value: 0.006GEE model
Comparison: Week 48p-value: 0.003GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: 0.007GEE model
Comparison: Week 216p-value: 0.005GEE model
Comparison: Week 240p-value: 0.006GEE model
Secondary
Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score
The Brief Fatigue Inventory (BFI) is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a 0 to 10 numerical rating scale with a recall period of 24 hours. Worst fatigue is defined as the answer to Question 3 in which participants rated their fatigue at its worst in the last 24 hours on a scale from 0 (no fatigue) to 10 (as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BFI measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 24 | -1.3 score on a scale | Standard Error 0.5 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 48 | -0.9 score on a scale | Standard Error 0.8 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 96 | -1.0 score on a scale | Standard Error 0.5 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 144 | -0.9 score on a scale | Standard Error 0.6 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 168 | -1.6 score on a scale | Standard Error 0.6 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 192 | -1.0 score on a scale | Standard Error 0.4 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 216 | -2.1 score on a scale | Standard Error 0.9 |
| Burosumab | Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score | Week 240 | -2.6 score on a scale | Standard Error 0.9 |
Comparison: Week 24p-value: 0.014GEE model
Comparison: Week 48p-value: 0.309GEE model
Comparison: Week 96p-value: 0.036GEE model
Comparison: Week 144p-value: 0.096GEE model
Comparison: Week 168p-value: 0.005GEE model
Comparison: Week 192p-value: 0.022GEE model
Comparison: Week 216p-value: 0.022GEE model
Comparison: Week 240p-value: 0.004GEE model
Secondary
Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score
The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours. Pain interference is defined as the average of 7 questions (9A through 9G) regarding the extent to which pain interfered with daily activities, including general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life in the last 24 hours, rated on a scale from 0 (does not interfere) to 10 (completely interferes). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 24 | -1.15 score on a scale | Standard Error 0.66 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 48 | -1.09 score on a scale | Standard Error 0.8 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 96 | -1.08 score on a scale | Standard Error 0.55 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 144 | -1.46 score on a scale | Standard Error 0.61 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 168 | -1.76 score on a scale | Standard Error 0.37 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 192 | -1.11 score on a scale | Standard Error 0.58 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 216 | -1.56 score on a scale | Standard Error 0.87 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score | Week 240 | -2.00 score on a scale | Standard Error 1.1 |
Comparison: Week 24p-value: 0.082GEE model
Comparison: Week 48p-value: 0.176GEE model
Comparison: Week 96p-value: 0.047GEE model
Comparison: Week 144p-value: 0.017GEE model
Comparison: Week 168p-value: 0GEE model
Comparison: Week 192p-value: 0.057GEE model
Comparison: Week 216p-value: 0.071GEE model
Comparison: Week 240p-value: 0.07GEE model
Secondary
Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score
The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours. Pain severity is defined as the average of 4 questions (Questions 3 through 6) assessing worst pain, least pain, average pain, and pain right now, rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). Mild pain is defined as a score of 1 to 4, moderate pain is defined as a score of 5 to 6, and severe pain is defined as a score of 7 to 10. A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 24 | -0.51 score on a scale | Standard Error 0.62 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 48 | -0.87 score on a scale | Standard Error 0.66 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 96 | -0.62 score on a scale | Standard Error 0.38 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 144 | -0.99 score on a scale | Standard Error 0.42 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 168 | -1.21 score on a scale | Standard Error 0.4 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 192 | -0.81 score on a scale | Standard Error 0.66 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 216 | -0.75 score on a scale | Standard Error 0.63 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score | Week 240 | -0.91 score on a scale | Standard Error 0.76 |
Comparison: Week 24p-value: 0.407GEE model
Comparison: Week 48p-value: 0.192GEE model
Comparison: Week 96p-value: 0.106GEE model
Comparison: Week 144p-value: 0.02GEE model
Comparison: Week 168p-value: 0.002GEE model
Comparison: Week 192p-value: 0.22GEE model
Comparison: Week 216p-value: 0.23GEE model
Comparison: Week 240p-value: 0.232GEE model
Secondary
Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score
The Brief Pain Inventory (BPI) is a self-reported, pain-specific questionnaire with a recall period of 24 hours. Worst pain is defined as the answer to Question 3, in which participants rated their pain at its worst in the last 24 hours on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative change from Baseline score indicates improvement. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BPI measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 24 | -0.6 score on a scale | Standard Error 0.7 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 48 | -0.9 score on a scale | Standard Error 0.7 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 96 | -0.7 score on a scale | Standard Error 0.4 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 144 | -1.1 score on a scale | Standard Error 0.6 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 168 | -0.9 score on a scale | Standard Error 0.7 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 192 | -0.9 score on a scale | Standard Error 0.6 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 216 | -0.9 score on a scale | Standard Error 0.8 |
| Burosumab | Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score | Week 240 | -0.9 score on a scale | Standard Error 0.9 |
Comparison: Week 24p-value: 0.41GEE model
Comparison: Week 48p-value: 0.21GEE model
Comparison: Week 96p-value: 0.06GEE model
Comparison: Week 144p-value: 0.076GEE model
Comparison: Week 168p-value: 0.171GEE model
Comparison: Week 192p-value: 0.141GEE model
Comparison: Week 216p-value: 0.263GEE model
Comparison: Week 240p-value: 0.32GEE model
Secondary
Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx)
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline CTx, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 216 | -140.71 pg/mL | Standard Error 94.55 |
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 24 | 212.91 pg/mL | Standard Error 125.76 |
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 48 | 97.02 pg/mL | Standard Error 80.1 |
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 96 | 6.55 pg/mL | Standard Error 63.66 |
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 144 | -19.28 pg/mL | Standard Error 38.49 |
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 168 | -100.84 pg/mL | Standard Error 49.31 |
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 192 | -200.40 pg/mL | Standard Error 65.8 |
| Burosumab | Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) | Week 240 | -92.14 pg/mL | Standard Error 102.27 |
Comparison: Week 24p-value: 0.09GEE model
Comparison: Week 48p-value: 0.226GEE model
Comparison: Week 96p-value: 0.918GEE model
Comparison: Week 144p-value: 0.616GEE model
Comparison: Week 168p-value: 0.041GEE model
Comparison: Week 192p-value: 0.002GEE model
Comparison: Week 216p-value: 0.137GEE model
Comparison: Week 240p-value: 0.368GEE model
Secondary
Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP)
FEP is the percentage of phosphorus filtered by the kidney that is excreted into urine, calculated as 100% \* (2-hour urine phosphorus\*serum creatinine)/(2-hour urine creatinine \* serum phosphorus). Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline FEP, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 24 | -0.14 percentage of phosphorus | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 48 | -0.14 percentage of phosphorus | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 96 | -0.10 percentage of phosphorus | Standard Error 0.03 |
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 144 | -0.15 percentage of phosphorus | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 168 | -0.14 percentage of phosphorus | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 192 | -0.14 percentage of phosphorus | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 216 | -0.15 percentage of phosphorus | Standard Error 0.01 |
| Burosumab | Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP) | Week 240 | -0.14 percentage of phosphorus | Standard Error 0.02 |
Comparison: Week 24p-value: <0.001GEE model
Comparison: Week 48p-value: <0.001GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: <0.001GEE model
Comparison: Week 240p-value: <0.001GEE model
Secondary
Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline free FGF23, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 216 | 704.87 pg/mL | Standard Error 115.3 |
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 24 | 624.91 pg/mL | Standard Error 101.89 |
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 48 | 578.07 pg/mL | Standard Error 95.37 |
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 96 | 736.59 pg/mL | Standard Error 139.18 |
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 144 | 801.69 pg/mL | Standard Error 103.41 |
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 168 | 787.16 pg/mL | Standard Error 95.52 |
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 192 | 717.71 pg/mL | Standard Error 115.99 |
| Burosumab | Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 240 | 625.16 pg/mL | Standard Error 125.93 |
Comparison: Week 24p-value: <0.001GEE model
Comparison: Week 48p-value: <0.001GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: <0.001GEE model
Comparison: Week 240p-value: <0.001GEE model
Secondary
Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements
To assess muscle strength, hand-held dynamometry was conducted using a standardized technique. Bilateral strength (defined as the average of the left and the right scores, measured in kilograms) of the elbow flexors and extensors was measured by the maximum voluntary isometric contraction against a dynamometer. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline strength measurements, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24 and 48
Population: TIO analysis set with available elbow dynamometry measurements at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements | Week 24 | 0.12 kg | Standard Error 0.512 |
| Burosumab | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements | Week 48 | 0.32 kg | Standard Error 0.753 |
| Elbow Extension | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements | Week 24 | 0.75 kg | Standard Error 0.704 |
| Elbow Extension | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements | Week 48 | 1.06 kg | Standard Error 0.76 |
Comparison: Week 24p-value: 0.8209GEE model
Comparison: Week 24p-value: 0.2851GEE model
Comparison: Week 48p-value: 0.6689GEE model
Comparison: Week 48p-value: 0.1612GEE model
Secondary
Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements
To assess muscle strength, hand-held dynamometry was conducted using a standardized technique. Bilateral strength (defined as the average of the left and the right scores, measured in kilograms) of the knee flexors and extensors was measured by the maximum voluntary isometric contraction against a dynamometer. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline strength measurements, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24 and 48
Population: TIO analysis set with available knee dynamometry measurements at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements | Week 48 | 1.21 kg | Standard Error 1.297 |
| Burosumab | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements | Week 24 | 0.94 kg | Standard Error 1.139 |
| Elbow Extension | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements | Week 24 | -0.89 kg | Standard Error 1.573 |
| Elbow Extension | Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements | Week 48 | 0.75 kg | Standard Error 1.158 |
Comparison: Week 24p-value: 0.4093GEE model
Comparison: Week 24p-value: 0.572GEE model
Comparison: Week 48p-value: 0.3501GEE model
Comparison: Week 48p-value: 0.5172GEE model
Secondary
Change From Baseline Over Time in Osteocalcin
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline osteocalcin, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 24 | 9.51 ng/mL | Standard Error 4.85 |
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 48 | 2.20 ng/mL | Standard Error 3.48 |
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 96 | -0.54 ng/mL | Standard Error 2.75 |
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 144 | -0.52 ng/mL | Standard Error 1.89 |
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 168 | -3.14 ng/mL | Standard Error 1.35 |
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 192 | -6.91 ng/mL | Standard Error 2.49 |
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 216 | -7.97 ng/mL | Standard Error 5.35 |
| Burosumab | Change From Baseline Over Time in Osteocalcin | Week 240 | -8.55 ng/mL | Standard Error 5.22 |
Comparison: Week 24p-value: 0.05GEE model
Comparison: Week 48p-value: 0.526GEE model
Comparison: Week 96p-value: 0.845GEE model
Comparison: Week 144p-value: 0.782GEE model
Comparison: Week 168p-value: 0.02GEE model
Comparison: Week 192p-value: 0.005GEE model
Comparison: Week 216p-value: 0.136GEE model
Comparison: Week 240p-value: 0.101GEE model
Secondary
Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP)
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline P1NP, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 24 | 34.07 ng/mL | Standard Error 10.9 |
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 48 | 7.73 ng/mL | Standard Error 7.05 |
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 96 | 11.28 ng/mL | Standard Error 15.56 |
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 144 | 1.21 ng/mL | Standard Error 5.55 |
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 168 | -12.04 ng/mL | Standard Error 3.36 |
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 192 | -11.93 ng/mL | Standard Error 8.11 |
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 216 | -7.53 ng/mL | Standard Error 14.58 |
| Burosumab | Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) | Week 240 | -1.67 ng/mL | Standard Error 14.39 |
Comparison: Week 24p-value: 0.002GEE model
Comparison: Week 48p-value: 0.273GEE model
Comparison: Week 96p-value: 0.469GEE model
Comparison: Week 144p-value: 0.828GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: 0.141GEE model
Comparison: Week 216p-value: 0.606GEE model
Comparison: Week 240p-value: 0.907GEE model
Secondary
Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR)
TmP/GFR measures renal phosphate reabsorption (the primary mechanism by which FGF23 regulates phosphate homeostasis) by comparing the fractional absorption of phosphate relative to the estimated rate of glomerular filtration. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline TmP/GFR, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 24 | 0.81 mg/dL | Standard Error 0.13 |
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 48 | 0.88 mg/dL | Standard Error 0.14 |
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 96 | 0.73 mg/dL | Standard Error 0.23 |
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 144 | 0.13 mg/dL | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 168 | 1.07 mg/dL | Standard Error 0.29 |
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 192 | 0.95 mg/dL | Standard Error 0.16 |
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 216 | 0.88 mg/dL | Standard Error 0.12 |
| Burosumab | Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) | Week 240 | 0.94 mg/dL | Standard Error 0.15 |
Comparison: Week 24p-value: <0.001GEE model
Comparison: Week 48p-value: <0.001GEE model
Comparison: Week 96p-value: 0.002GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: <0.001GEE model
Comparison: Week 240p-value: <0.001GEE model
Secondary
Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration
Least squares (LS) means and standard errors (SE) were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 1,25(OH)2D, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 24 | 9.90 pg/mL | Standard Error 4.1 |
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 48 | 10.49 pg/mL | Standard Error 4.82 |
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 96 | 4.28 pg/mL | Standard Error 3.8 |
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 144 | 3.15 pg/mL | Standard Error 3.34 |
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 168 | 4.91 pg/mL | Standard Error 3.94 |
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 192 | 0.67 pg/mL | Standard Error 4.19 |
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 216 | 9.78 pg/mL | Standard Error 3.04 |
| Burosumab | Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration | Week 240 | 6.56 pg/mL | Standard Error 3.19 |
Comparison: Week 24p-value: 0.016GEE model
Comparison: Week 48p-value: 0.03GEE model
Comparison: Week 96p-value: 0.259GEE model
Comparison: Week 144p-value: 0.346GEE model
Comparison: Week 168p-value: 0.213GEE model
Comparison: Week 192p-value: 0.873GEE model
Comparison: Week 216p-value: 0.001GEE model
Comparison: Week 240p-value: 0.04GEE model
Secondary
Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline ALP, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 24 | -1.68 U/L | Standard Error 10.91 |
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 48 | -20.36 U/L | Standard Error 11.68 |
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 96 | -38.23 U/L | Standard Error 11.9 |
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 144 | -57.45 U/L | Standard Error 10.97 |
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 168 | -62.80 U/L | Standard Error 12.35 |
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 192 | -60.40 U/L | Standard Error 12.41 |
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 216 | -50.14 U/L | Standard Error 26.09 |
| Burosumab | Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) | Week 240 | -49.71 U/L | Standard Error 24.35 |
Comparison: Week 24p-value: 0.878GEE model
Comparison: Week 48p-value: 0.081GEE model
Comparison: Week 96p-value: 0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: 0.055GEE model
Comparison: Week 240p-value: 0.041GEE model
Secondary
Change From Baseline Over Time in Sit-to-Stand (STS) Test
The STS test measures lower extremity strength and mobility as a participant moves repeatedly from a seated position to standing. This study used a modified STS test that allowed participants to use the arms of the chair to help them stand and sit if necessary. The number of sit-to-stand repetitions performed in a 30-second period was recorded. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24 and 48
Population: TIO analysis set with available STS data at each time point; One participant did not perform the test at Baseline as it was not included in the original protocol, and 2 participants were unable to perform the test due to underlying medical issues.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Sit-to-Stand (STS) Test | Week 24 | 1.5 sit-to-stand repetitions | Standard Error 0.54 |
| Burosumab | Change From Baseline Over Time in Sit-to-Stand (STS) Test | Week 48 | 1.6 sit-to-stand repetitions | Standard Error 0.5 |
Comparison: Week 24p-value: 0.0046GEE model
Comparison: Week 48p-value: 0.0012GEE model
Secondary
Change From Baseline Over Time in Six-Minute Walk Test (6MWT)
The 6MWT is a commonly used measure of mobility and was conducted in accordance with general principles set forth in the American Thoracic Society guidelines (ATS 2002). Participants were instructed to walk the length of a pre-measured course for 6 consecutive minutes (assistive devices could be used). The total distance walked at the end of 6 minutes was recorded in meters. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 6MWT measurement, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24 and 48
Population: TIO analysis set with available 6MWT measurements at Baseline and each time point. Six participants did not perform the test at Baseline as it was not included in the original protocol, and 2 participants were unable to perform the test due to underlying medical issues.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Six-Minute Walk Test (6MWT) | Week 24 | 19.5 meters | Standard Error 15.64 |
| Burosumab | Change From Baseline Over Time in Six-Minute Walk Test (6MWT) | Week 48 | 25.5 meters | Standard Error 16.58 |
Comparison: Week 24p-value: 0.2125GEE model
Comparison: Week 48p-value: 0.1241GEE model
Secondary
Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration
Total FGF23 included free FGF23 and FGF23 bound to burosumab. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline total FGF23, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 144 | 275758.40 pg/mL | Standard Error 102349.79 |
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 24 | 246335.35 pg/mL | Standard Error 61089.98 |
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 48 | 180511.74 pg/mL | Standard Error 33529.14 |
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 96 | 331267.40 pg/mL | Standard Error 103226.37 |
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 168 | 185769.23 pg/mL | Standard Error 65423.93 |
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 192 | 234826.20 pg/mL | Standard Error 82198.24 |
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 216 | 254359.96 pg/mL | Standard Error 81615.67 |
| Burosumab | Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration | Week 240 | 210119.10 pg/mL | Standard Error 76610.5 |
Comparison: Week 24p-value: <0.0001GEE model
Comparison: Week 48p-value: <0.0001GEE model
Comparison: Week 96p-value: 0.001GEE model
Comparison: Week 144p-value: 0.007GEE model
Comparison: Week 168p-value: 0.005GEE model
Comparison: Week 192p-value: 0.004GEE model
Comparison: Week 216p-value: 0.002GEE model
Comparison: Week 240p-value: 0.006GEE model
Secondary
Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP)
Tubular reabsorption of phosphate (TRP) is the fraction of filtered phosphorus that is reabsorbed by renal tubules. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline TRP, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 24 | 0.13 fraction of phosphorus reabsorbed | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 48 | 0.14 fraction of phosphorus reabsorbed | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 96 | 0.10 fraction of phosphorus reabsorbed | Standard Error 0.03 |
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 144 | 0.13 fraction of phosphorus reabsorbed | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 168 | 0.12 fraction of phosphorus reabsorbed | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 192 | 0.14 fraction of phosphorus reabsorbed | Standard Error 0.02 |
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 216 | 0.14 fraction of phosphorus reabsorbed | Standard Error 0.01 |
| Burosumab | Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) | Week 240 | 0.12 fraction of phosphorus reabsorbed | Standard Error 0.02 |
Comparison: Week 24p-value: <0.001GEE model
Comparison: Week 48p-value: <0.001GEE model
Comparison: Week 96p-value: 0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: <0.001GEE model
Comparison: Week 240p-value: <0.001GEE model
Secondary
Change From Baseline Over Time in Weighted Arm Lift (WAL) Test
The Weighted arm lift (WAL) test assesses upper extremity strength, mobility and reaching ability. The test was administered bilaterally to determine the number of times the participant could raise a 1 kg weight above the head in a 30-second period. The number of repetitions completed with each arm was recorded. Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline WAL measurements, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24 and 48
Population: TIO analysis set with available WAL measurements at Baseline and each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Change From Baseline Over Time in Weighted Arm Lift (WAL) Test | Week 24 | -0.5 arm lifts | Standard Error 1.09 |
| Burosumab | Change From Baseline Over Time in Weighted Arm Lift (WAL) Test | Week 48 | 0.1 arm lifts | Standard Error 1.25 |
| Elbow Extension | Change From Baseline Over Time in Weighted Arm Lift (WAL) Test | Week 24 | 0.6 arm lifts | Standard Error 0.89 |
| Elbow Extension | Change From Baseline Over Time in Weighted Arm Lift (WAL) Test | Week 48 | 1.7 arm lifts | Standard Error 1.17 |
Comparison: Week 24p-value: 0.6475GEE model
Comparison: Week 24p-value: 0.5319GEE model
Comparison: Week 48p-value: 0.9206GEE model
Comparison: Week 48p-value: 0.153GEE model
Secondary
Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
Mean change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24).
Time frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
Population: TIO analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Burosumab | Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 | 0.550 mg/dL | Standard Deviation 0.426 |
Secondary
Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24
Mean change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).
Time frame: Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)
Population: TIO analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Burosumab | Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 | 1.039 mg/dL | Standard Deviation 0.5622 |
Secondary
Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24
The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (2.5 mg/dL \[0.81 mmol/L\]) at the end of the dose interval (4 weeks post-dose, prior to the next dose), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24).
Time frame: End of each dose interval from Baseline to Week 24 (Weeks 4, 8, 12, 16, 20, and 24)
Population: TIO analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Burosumab | Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24 | 21.4 percentage of participants |
Secondary
Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24
Mean percent change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).
Time frame: Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)
Population: TIO analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Burosumab | Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 | 69.77 percent change | Standard Deviation 43.743 |
Secondary
Percent Change From Baseline Over Time in BALP
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline BALP, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 24 | 5.15 percent change | Standard Error 13.06 |
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 48 | -16.56 percent change | Standard Error 8.35 |
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 96 | -30.40 percent change | Standard Error 8.57 |
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 144 | -35.82 percent change | Standard Error 9.47 |
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 168 | -40.97 percent change | Standard Error 9.6 |
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 192 | -41.11 percent change | Standard Error 9.93 |
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 216 | -28.41 percent change | Standard Error 20.71 |
| Burosumab | Percent Change From Baseline Over Time in BALP | Week 240 | -42.27 percent change | Standard Error 11.65 |
Comparison: Week 24p-value: 0.694GEE model
Comparison: Week 48p-value: 0.047GEE model
Comparison: Week 96p-value: <0.001GEE model
Comparison: Week 144p-value: <0.001GEE model
Comparison: Week 168p-value: <0.001GEE model
Comparison: Week 192p-value: <0.001GEE model
Comparison: Week 216p-value: 0.17GEE model
Comparison: Week 240p-value: <0.001GEE model
Secondary
Percent Change From Baseline Over Time in CTx
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline CTx, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 24 | 33.77 percent change | Standard Error 14.33 |
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 48 | 31.05 percent change | Standard Error 20.22 |
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 96 | 11.96 percent change | Standard Error 12.05 |
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 144 | 10.92 percent change | Standard Error 8.86 |
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 168 | -2.23 percent change | Standard Error 8.29 |
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 192 | -15.90 percent change | Standard Error 11.21 |
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 216 | -10.53 percent change | Standard Error 7.4 |
| Burosumab | Percent Change From Baseline Over Time in CTx | Week 240 | -5.68 percent change | Standard Error 10.26 |
Comparison: Week 24p-value: 0.018GEE model
Comparison: Week 48p-value: 0.133GEE model
Comparison: Week 96p-value: 0.321GEE model
Comparison: Week 144p-value: 0.218GEE model
Comparison: Week 168p-value: 0.788GEE model
Comparison: Week 192p-value: 0.156GEE model
Comparison: Week 216p-value: 0.155GEE model
Comparison: Week 240p-value: 0.58GEE model
Secondary
Percent Change From Baseline Over Time in Osteocalcin
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline osteocalcin, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 24 | 41.49 percent change | Standard Error 12.19 |
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 48 | 16.28 percent change | Standard Error 13.79 |
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 96 | 15.04 percent change | Standard Error 14.1 |
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 144 | 14.08 percent change | Standard Error 8.38 |
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 168 | -0.98 percent change | Standard Error 7.11 |
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 192 | -19.67 percent change | Standard Error 10.42 |
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 216 | -5.65 percent change | Standard Error 11.48 |
| Burosumab | Percent Change From Baseline Over Time in Osteocalcin | Week 240 | -8.37 percent change | Standard Error 10.17 |
Comparison: Week 24p-value: <0.001GEE model
Comparison: Week 48p-value: 0.238GEE model
Comparison: Week 96p-value: 0.286GEE model
Comparison: Week 144p-value: 0.093GEE model
Comparison: Week 168p-value: 0.89GEE model
Comparison: Week 192p-value: 0.059GEE model
Comparison: Week 216p-value: 0.623GEE model
Comparison: Week 240p-value: 0.411GEE model
Secondary
Percent Change From Baseline Over Time in P1NP
Least squares means and standard errors were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline P1NP, with compound symmetry covariance structure.
Time frame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Population: TIO analysis set participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 24 | 53.71 percent change | Standard Error 16.35 |
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 48 | 15.64 percent change | Standard Error 10.84 |
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 96 | 18.09 percent change | Standard Error 20.29 |
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 144 | 13.65 percent change | Standard Error 8.68 |
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 168 | -12.40 percent change | Standard Error 4.98 |
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 192 | 0.93 percent change | Standard Error 19.78 |
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 216 | -7.58 percent change | Standard Error 17.45 |
| Burosumab | Percent Change From Baseline Over Time in P1NP | Week 240 | 4.47 percent change | Standard Error 16.82 |
Comparison: Week 24p-value: 0.001GEE model
Comparison: Week 48p-value: 0.149GEE model
Comparison: Week 96p-value: 0.372GEE model
Comparison: Week 144p-value: 0.116GEE model
Comparison: Week 168p-value: 0.013GEE model
Comparison: Week 192p-value: 0.962GEE model
Comparison: Week 216p-value: 0.664GEE model
Comparison: Week 240p-value: 0.79GEE model
Secondary
Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
Mean percent change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24).
Time frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
Population: TIO analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Burosumab | Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 | 38.56 percent change | Standard Deviation 33.027 |
Secondary
Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24
Serum phosphorus level versus time AUC was calculated using the trapezoidal rule. Time-adjusted AUC was calculated by dividing the AUC by duration of time included in AUC calculation.
Time frame: Pre-dose on Day 1 and at Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 21, 22, and 24
Population: TIO analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Burosumab | Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24 | 2.36 mg/dL | Standard Deviation 0.632 |
Other Pre-specified
Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death).
Time frame: From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days.
Population: TIO analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious adverse events (SAEs) | 8 Participants |
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAE leading to study discontinuation | 0 Participants |
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Any adverse event | 14 Participants |
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Related adverse events | 9 Participants |
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious related adverse events | 0 Participants |
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Grade 3 or 4 adverse event | 8 Participants |
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAE leading to treatment discontinuation | 1 Participants |
| Burosumab | Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAE leading to death | 2 Participants |
Other Pre-specified
Number of Participants With Anti-burosumab Antibodies
Time frame: From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days.
Population: TIO analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Burosumab | Number of Participants With Anti-burosumab Antibodies | Anti-burosumab binding antibodies | 2 Participants |
| Burosumab | Number of Participants With Anti-burosumab Antibodies | Anti-burosumab neutralizing antibodies | 0 Participants |