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

Phase 2

Completed

Conditions: X-linked Hypophosphatemia

Interventions: Biological: burosumab

Registration Number: NCT02163577

Lead Sponsor: Kyowa Kirin, Inc.

Brief Summary: The objectives of the study are to:

* Identify a dose and dosing regimen of burosumab, based on safety and pharmacodynamic (PD) effect, in pediatric XLH participants

* Establish the safety profile of burosumab for the treatment of children with XLH including ectopic mineralization risk, cardiovascular effects, and immunogenicity profile

* Characterize the pharmacokinetic (PK)/PD profile of the KRN23 doses tested in the monthly (Q4) and biweekly (Q2) dose regimens in pediatric XLH patients

* Determine the PD effects of burosumab treatment on markers of bone health in pediatric XLH patients

* Obtain a preliminary assessment of the clinical effects of burosumab on bone health and deformity, muscle strength, and motor function

* Obtain a preliminary assessment of the effects of burosumab on participant-reported outcomes, including pain, disability, and quality of life in pediatric XLH patients

* Evaluate the long-term safety and efficacy of burosumab

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Burosumab Q4W Then Q2W	burosumab	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.
Burosumab Q2W	burosumab	Burosumab subcutaneous (SC) injections every 2 weeks (Q2W). Dose was determined by the participant's weight and prescribed dose by their study doctor.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (9): University of California San Francisco
🇺🇸
San Francisco, California, United States
Bicetre Hospital
🇫🇷
Le Kremlin- Bicetre, France
Yale University School of Medicine
🇺🇸
New Haven, Connecticut, United States
Birmingham Children's University
🇬🇧
Birmingham, United Kingdom
Indiana University Hospital
🇺🇸
Indianapolis, Indiana, United States
Royal Manchester Hospital
🇬🇧
Manchester, Lancashire, United Kingdom
Shriners Hospital for Children
🇺🇸
Saint Louis, Missouri, United States
Great Ormond Street Hospital
🇬🇧
London, United Kingdom
University Medical Center Groningen
🇳🇱
Groningen, Netherlands