Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02750618
Recruitment Status : Active, not recruiting
First Posted : April 25, 2016
Results First Posted : June 19, 2018
Last Update Posted : January 8, 2019
Sponsor:
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

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 ...

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
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
Estimated Study Completion Date : September 2019


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




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 the signing of informed consent through the Week 64 data cutoff ]
    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) Global 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 Global 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 in Recumbent Length/Standing Height From Baseline Up to Week 64 [ Time Frame: Baseline, Weeks 12, 24, 40, 64 ]
  8. Change From Baseline in Recumbent Length/Standing Height From Baseline to Weeks 12, 24, 40, and 64 as Assessed by Height-for-Age Z-Scores [ Time Frame: Baseline, Weeks 12, 24, 40, 64 ]
    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 in Recumbent Length/Standing Height From Baseline to Weeks 12, 24, 40, and 64 as Assessed by Percentiles [ Time Frame: Baseline, Weeks 12, 24, 40, 64 ]
  10. Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP) [ Time Frame: Baseline, Weeks 4, 12, 20, 40, 48, 56, 64 ]
    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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02750618


Locations
Layout table for location information
United States, Connecticut
Yale 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
Layout table for investigator information
Study Director: Medical Director Ultragenyx Pharmaceutical Inc
  Study Documents (Full-Text)

Documents provided by Ultragenyx Pharmaceutical Inc:
Study Protocol  [PDF] March 28, 2016
Statistical Analysis Plan  [PDF] November 29, 2016


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02750618     History of Changes
Other Study ID Numbers: UX023-CL205
First Posted: April 25, 2016    Key Record Dates
Results First Posted: June 19, 2018
Last Update Posted: January 8, 2019
Last Verified: December 2018

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Additional relevant MeSH terms:
Layout table for 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
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs