Clinical trial NCT02163577: Study of KRN23 (Burosumab), a Recombinant Fully Human Monoclonal Antibody Against Fibroblast Growth Factor 23 (FGF23), in Pediatric Subjects With X-linked Hypophosphatemia (XLH)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: X-linked Hypophosphatemia
Keywords: X-linked hypophosphatemia
XLH
FGF23
KRN23
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Kyowa Kirin Co., Ltd.
First posted: 2014-06-13
Enrollment: 52
Sex: ALL
Minimum age (years): 5
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: Inclusion

1. Male or female, aged 5 - 12 years, inclusive, with open growth plates
2. Tanner stage of 2 or less based on breast and testicular development
3. Diagnosis of XLH supported by ONE of the following:

   * Confirmed Phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance
   * Serum FGF23 level \> 30 pg/mL by Kainos assay
4. Biochemical findings associated with XLH including:

   * Serum phosphorus ≤ 2.8 mg/dL (0.904 mmol/L)\*
   * Serum creatinine within age-adjusted normal range\*
5. Standing height \< 50th percentile for age and gender using local normative data.
6. Radiographic evidence of active bone disease including rickets in the wrists and/or knees, AND/OR femoral/tibial bowing, OR, for expansion subjects, a Rickets Severity Score (RSS) score in the knee of at least 1.5 as determined by central read.
7. Willing to provide access to prior medical records for the collection of historical growth, biochemical and radiographic data, and disease history.
8. Provide written or verbal assent (if possible) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.
9. Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments.
10. Females who have reached menarche must have a negative pregnancy test at Screening and undergo additional pregnancy testing during the study. If sexually active, male and female subjects must be willing to use an acceptable method of contraception for the duration of the study.

    * Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2

Exclusion

1. Use of a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, alfacalcidiol, and paricalcitol) within 14 days prior to Screening Visit 2; washout will take place during the Screening Period
2. Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take place during the Screening Period
3. Use of calcimimetics, aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, and thiazides within 7 days prior to Screening Visit 1
4. Use of growth hormone therapy within 3 months before Screening Visit 1
5. Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1
6. Presence of nephrocalcinosis on renal ultrasound graded ≥ 3 based on the following scale: 0 = Normal 1 = Faint hyperechogenic rim around the medullary pyramids 2 = More intense echogenic rim with echoes faintly filling the entire pyramid 3 = Uniformly intense echoes throughout the pyramid 4 = Stone formation: solitary focus of echoes at the tip of the pyramid
7. Planned or recommended orthopedic surgery, including staples, 8-plates or osteotomy, within the clinical trial period
8. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits \*
9. Evidence of tertiary hyperparathyroidism as determined by the Investigator
10. Use of medication to suppress parathyroid hormone (PTH) (e.g. Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening Visit 1
11. Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study
12. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
13. Previously diagnosed with human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody
14. History of recurrent infection or predisposition to infection, or of known immunodeficiency
15. Use of a therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 or history of allergic or anaphylactic reactions to any monoclonal antibody
16. Presence or history of any hypersensitivity to recombinant human immunoglobulin G1 (IgG1) monoclonal antibody to FGF23 (burosumab) excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
17. Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments

    * Criteria to be determined based on overnight fasting (minimum 4 hours) values collected at Screening Visit 2

Primary outcomes:
measure: Change From Baseline in RSS Total Score Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Serum Phosphorus Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Serum 1,25(OH)2D Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in TmP/GFR Over Time
timeFrame: Baseline, Week 40, 64, 160
Secondary outcomes:
measure: Change From Baseline in RSS Knee Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in RSS Wrist Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Radiographic Global Impression of Change (RGI-C) Global Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: RGI-C Knee Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: RGI-C Wrist Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Growth Velocity Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Standing Height Z Score Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Growth (Standing Height) Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Growth (Sitting Height) Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Growth (Arm Length) Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in Growth (Leg Length) Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: 6MWT Distance (Predicted Percent of Normal) Change From Baseline Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in FEP Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in P1NP Over Time
timeFrame: Baseline, Week 40, 64
measure: Change From Baseline in CTx Over Time
timeFrame: Baseline, Week 40, 64
measure: Change From Baseline in ALP Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Change From Baseline in BALP Over Time
timeFrame: Baseline, Week 40, 64, 160
measure: Serum Pre-Dose Concentrations of Burosumab
timeFrame: Week 40, 64, 160
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)
timeFrame: Up to 216 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Indianapolis
country: United States
facility: Indiana University Hospital
state: Indiana
city: Saint Louis
country: United States
facility: Shriners Hospital for Children
state: Missouri
city: Le Kremlin- Bicetre
country: France
facility: Bicetre Hospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Manchester
country: United Kingdom
facility: Royal Manchester Hospital
state: Lancashire
city: Birmingham
country: United Kingdom
facility: Birmingham Children's University
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Linglart A, Imel EA, Whyte MP, Portale AA, Hogler W, Boot AM, Padidela R, Van't Hoff W, Gottesman GS, Chen A, Skrinar A, Scott Roberts M, Carpenter TO. Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia. J Clin Endocrinol Metab. 2022 Feb 17;107(3):813-824. doi: 10.1210/clinem/dgab729.
citation: Mao M, Carpenter TO, Whyte MP, Skrinar A, Chen CY, San Martin J, Rogol AD. Growth Curves for Children with X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2020 Oct 1;105(10):3243-9. doi: 10.1210/clinem/dgaa495.
citation: Carpenter TO, Whyte MP, Imel EA, Boot AM, Hogler W, Linglart A, Padidela R, Van't Hoff W, Mao M, Chen CY, Skrinar A, Kakkis E, San Martin J, Portale AA. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018 May 24;378(21):1987-1998. doi: 10.1056/NEJMoa1714641.