Study of KRN23 (Burosumab), a Recombinant Fully Human Monoclonal Antibody Against Fibroblast Growth Factor 23 (FGF23), in Pediatric Subjects With X-linked Hypophosphatemia (XLH)

Study Overview
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Brief Summary
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The objectives of the study are to: Identify a dose and dosing regimen of burosumab, based on safety and pharmacodynamic (PD) effect, in pediatric XLH participants Establish the safety profile of burosumab for the treatment of children with XLH including ectopic mineralization risk, cardiovascular effects, and immunogenicity profile Characterize the pharmacokinetic (PK)/PD profile of the KRN23 doses tested in the monthly (Q4) and biweekly (Q2) dose regimens in pediatric XLH patients Determine the PD effects of burosumab treatment on markers of bone health in pediatric XLH patients Obtain a preliminary assessment of the clinical effects of burosumab on bone health and deformity, muscle strength, and motor function Obtain a preliminary assessment of the effects of burosumab on participant-reported outcomes, including pain, disability, and quality of life in pediatric XLH patients Evaluate the long-term safety and efficacy of burosumab

Official Title
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A Randomized, Open-Label, Dose Finding, Phase 2 Study to Assess the Pharmacodynamics and Safety of the Anti-FGF23 Antibody, KRN23, in Pediatric Patients With X-linked Hypophosphatemia (XLH)

Conditions
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X-linked Hypophosphatemia

Intervention / Treatment
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* Biological: burosumab


Participation Criteria
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Eligibility Criteria
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Inclusion Male or female, aged 5 - 12 years, inclusive, with open growth plates Tanner stage of 2 or less based on breast and testicular development Diagnosis of XLH supported by ONE of the following: Confirmed Phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance Serum FGF23 level > 30 pg/mL by Kainos assay Biochemical findings associated with XLH including: Serum phosphorus ≤ 2.8 mg/dL (0.904 mmol/L)* Serum creatinine within age-adjusted normal range* Standing height < 50th percentile for age and gender using local normative data. Radiographic evidence of active bone disease including rickets in the wrists and/or knees, AND/OR femoral/tibial bowing, OR, for expansion subjects, a Rickets Severity Score (RSS) score in the knee of at least 1.5 as determined by central read. Willing to provide access to prior medical records for the collection of historical growth, biochemical and radiographic data, and disease history. Provide written or verbal assent (if possible) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures. Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments. Females who have reached menarche must have a negative pregnancy test at Screening and undergo additional pregnancy testing during the study. If sexually active, male and female subjects must be willing to use an acceptable method of contraception for the duration of the study. Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2 Exclusion Use of a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, alfacalcidiol, and paricalcitol) within 14 days prior to Screening Visit 2; washout will take place during the Screening Period Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take place during the Screening Period Use of calcimimetics, aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, and thiazides within 7 days prior to Screening Visit 1 Use of growth hormone therapy within 3 months before Screening Visit 1 Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1 Presence of nephrocalcinosis on renal ultrasound graded ≥ 3 based on the following scale: 0 = Normal 1 = Faint hyperechogenic rim around the medullary pyramids 2 = More intense echogenic rim with echoes faintly filling the entire pyramid 3 = Uniformly intense echoes throughout the pyramid 4 = Stone formation: solitary focus of echoes at the tip of the pyramid Planned or recommended orthopedic surgery, including staples, 8-plates or osteotomy, within the clinical trial period Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits * Evidence of tertiary hyperparathyroidism as determined by the Investigator Use of medication to suppress parathyroid hormone (PTH) (e.g. Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening Visit 1 Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study Presence of a concurrent disease or condition that would interfere with study participation or affect safety Previously diagnosed with human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody History of recurrent infection or predisposition to infection, or of known immunodeficiency Use of a therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 or history of allergic or anaphylactic reactions to any monoclonal antibody Presence or history of any hypersensitivity to recombinant human immunoglobulin G1 (IgG1) monoclonal antibody to FGF23 (burosumab) excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Burosumab Q2W<br>Burosumab subcutaneous (SC) injections every 2 weeks (Q2W). Dose was determined by the participant's weight and prescribed dose by their study doctor. | Biological: burosumab<br>* solution for SC injection<br>* Other names: UX023;|
| Experimental: Burosumab Q4W Then Q2W<br>Burosumab SC injections every 4 weeks (Q4W). Dose was determined by the participant's weight and prescribed dose by their study doctor. Participants in Q4W were to switch to Q2W beginning with Week 64 dosing. | Biological: burosumab<br>* solution for SC injection<br>* Other names: UX023;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in RSS Total Score Over Time | The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Serum Phosphorus Over Time |  | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Serum 1,25(OH)2D Over Time |  | Baseline, Week 40, 64, 160 | 
| Change From Baseline in TmP/GFR Over Time | Data for urinary phosphorus and TRP were used in calculation TmP/GFR. | Baseline, Week 40, 64, 160 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in RSS Knee Scores Over Time | The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in RSS Wrist Scores Over Time | The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. | Baseline, Week 40, 64, 160 | 
| Radiographic Global Impression of Change (RGI-C) Global Scores Over Time | Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). | Baseline, Week 40, 64, 160 | 
| RGI-C Knee Scores Over Time | Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). | Baseline, Week 40, 64, 160 | 
| RGI-C Wrist Scores Over Time | Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Growth Velocity Over Time |  | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Standing Height Z Score Over Time | Standing height Z scores are measures of height adjusted for a child's age and sex. The Z score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Growth (Standing Height) Over Time |  | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Growth (Sitting Height) Over Time |  | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Growth (Arm Length) Over Time |  | Baseline, Week 40, 64, 160 | 
| Change From Baseline in Growth (Leg Length) Over Time |  | Baseline, Week 40, 64, 160 | 
| 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time | The total distance walked (meters) in a 6-minute period was measured. The percent of predicted values were calculated using published normative data based on age, gender, and height (Geiger et al. 2007). | Baseline, Week 40, 64, 160 | 
| Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time | The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in FEP Over Time | FEP is defined as 100% × (urine phosphorus × serum creatinine)/(urine creatinine × serum phosphorus), where the 2-hour urine sample was used for urine phosphorus and urine creatinine. | Baseline, Week 40, 64, 160 | 
| Change From Baseline in P1NP Over Time |  | Baseline, Week 40, 64 | 
| Change From Baseline in CTx Over Time |  | Baseline, Week 40, 64 | 
| Change From Baseline in ALP Over Time |  | Baseline, Week 40, 64, 160 | 
| Change From Baseline in BALP Over Time |  | Baseline, Week 40, 64, 160 | 
| Serum Pre-Dose Concentrations of Burosumab |  | Week 40, 64, 160 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE is defined as an AE or suspected adverse reaction that at any dose results in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect. Severity was graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). TEAEs are defined as AEs with onset on or after the time of initiation of study drug administration. | Up to 216 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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X-linked hypophosphatemia, XLH, FGF23, KRN23