Study of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)

• ClinicalTrials.gov Identifier: NCT02750618
• Recruitment Status: Completed
• First Posted: April 25, 2016
• Results First Posted: June 19, 2018
• Last Update Posted: March 31, 2020
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Study Description

Brief Summary:

The primary objectives of the study are to:

• Establish the safety profile of KRN23 for the treatment of XLH in children between 1 and 4 years old
• Determine the PD effects of KRN23 treatment on serum phosphorus and other PD markers that reflect the status of phosphate homeostasis in children between 1 and 4 years old with XLH

Condition or disease	Intervention/treatment	Phase
X-Linked Hypophosphatemia	Biological: Burosumab	Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
• Actual Study Start Date: May 5, 2016
• Actual Primary Completion Date: April 20, 2017
• Actual Study Completion Date: September 10, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Burosumab Q2W; Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks.	Biological: Burosumab; solution for subcutaneous injection; Other Names: KRN23; Crysvita®; UX023

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline at Week 40 in Serum Phosphorus [ Time Frame: Baseline, Week 40 ]
   The Generalized Estimation Equation (GEE) model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
2. Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation [ Time Frame: From first dose of study drug through the end of the study (Week 160). Maximum duration of exposure to study drug was 160 weeks. ]
   An 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).

Secondary Outcome Measures :

1. Radiographic Global Impression of Change (RGI-C) Score at Week 40 [ Time Frame: Week 40 ]
   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). The Analysis of Covariance (ANCOVA) model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
2. RGI-C Score at Week 64 [ Time Frame: Week 64 ]
   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). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
3. Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score [ Time Frame: Baseline, Week 40 ]
   The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, 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.The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
4. Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score [ Time Frame: Baseline, Week 64 ]
   The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. The GEE model includes the change from baseline in RSS as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
5. RGI-C Lower Limb Deformity Score at Week 40 [ Time Frame: Week 40 ]
   Changes in the severity of lower extremity skeletal abnormalities 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). The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
6. RGI-C Lower Limb Deformity Score at Week 64 [ Time Frame: Week 64 ]
   Changes in the severity of lower extremity skeletal abnormalities 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). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
7. Change From Baseline Over Time in Recumbent Length/Standing Height [ Time Frame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 ]
8. Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores [ Time Frame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 ]
   Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.
9. Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles [ Time Frame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160 ]
10. Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) [ Time Frame: Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160 ]
    The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
11. Percent Change From Baseline Over Time in Serum ALP [ Time Frame: Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160 ]

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 4 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female, aged ≥1 year and <5 years

2. Diagnosis of XLH supported by ONE or more 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 fibroblast growth factor 23 (FGF23) level > 30 pg/mL by Kainos assay

3. Biochemical findings associated with XLH including:

   • Serum phosphorus < 3.0 mg/dL (0.97 mmol/L)
   • Serum creatinine within age-adjusted normal range
4. Radiographic evidence of rickets
5. Willing to provide access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history
6. Provide written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures
7. 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

Exclusion Criteria:

1. Unwilling to stop treatment with oral phosphate and/or pharmacologic vitamin D metabolite or analog (e.g. calcitriol, alfacalcidol) during the screening period and for the duration of the study
2. Presence of nephrocalcinosis on renal ultrasound grade 4 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
3. Planned or recommended orthopedic surgery including staples, 8-plates or osteotomy, within the clinical trial period
4. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
5. 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
6. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
7. History of recurrent infection or predisposition to infection, or of known immunodeficiency
8. 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

Contacts and Locations

Locations

United States, Connecticut

Yale University School of Medicine

New Haven, Connecticut, United States, 06510

United States, Indiana

Indiana University School of Medicine

Indianapolis, Indiana, United States, 46202

United States, Missouri

Shriners Hospital for Children

Saint Louis, Missouri, United States, 63110

Sponsors and Collaborators

Ultragenyx Pharmaceutical Inc

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

  Study Documents (Full-Text)

Documents provided by Ultragenyx Pharmaceutical Inc:

Statistical Analysis Plan  [PDF] November 29, 2016

Study Protocol  [PDF] June 12, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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). pii: dgaa495. doi: 10.1210/clinem/dgaa495.

Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, Imel EA. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019 Mar;7(3):189-199. doi: 10.1016/S2213-8587(18)30338-3. Epub 2019 Jan 9.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02750618
• Other Study ID Numbers: UX023-CL205
• First Posted: April 25, 2016
• Results First Posted: June 19, 2018
• Last Update Posted: March 31, 2020
• Last Verified: March 2020

• Studies a U.S. FDA-regulated Drug Product: Yes

Additional relevant MeSH terms:

Familial Hypophosphatemic Rickets; Hypophosphatemia; Phosphorus Metabolism Disorders; Metabolic Diseases; Rickets, Hypophosphatemic; Rickets; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Hypophosphatemia, Familial; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Calcium Metabolism Disorders; Vitamin D Deficiency; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders