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Efficacy and Safety of KRN23 Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With X Linked Hypophosphatemia (XLH) (PIXLES)

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ClinicalTrials.gov Identifier: NCT02915705
Recruitment Status : Active, not recruiting
First Posted : September 27, 2016
Last Update Posted : September 3, 2018
Sponsor:
Collaborator:
Kyowa Hakko Kirin Co., Ltd
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Brief Summary:
The primary objective of this study is to evaluate the effect of KRN23 therapy in improving rickets in children with XLH compared with active control (oral phosphate/active vitamin D).

Condition or disease Intervention/treatment Phase
X-Linked Hypophosphatemia Biological: burosumab Drug: oral phosphate Drug: active vitamin D Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 61 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Phase 3 Study to Assess the Efficacy and Safety of KRN23 Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With X Linked Hypophosphatemia (XLH)
Actual Study Start Date : September 8, 2016
Actual Primary Completion Date : February 12, 2018
Estimated Study Completion Date : June 2019


Arm Intervention/treatment
Experimental: burosumab
0.8 mg/kg starting dose, administered every 2 weeks by subcutaneous injection
Biological: burosumab
Solution for SC injection
Other Names:
  • KRN23
  • Crysvita ®
  • UX023

Active Comparator: Active Control

Multiple daily doses of oral phosphate and active vitamin D therapy, individualized for each subject at the Investigator's discretion.

In the study extension period, eligible subjects that cross-over onto burosumab will receive 0.8 mg/kg starting dose, administered every 2 weeks by subcutaneous injection.

Biological: burosumab
Solution for SC injection
Other Names:
  • KRN23
  • Crysvita ®
  • UX023

Drug: oral phosphate
Drug: active vitamin D



Primary Outcome Measures :
  1. Change From Baseline in Rickets as Assessed by the Radiographic Global Impression of Change (RGI-C) Global Score at Week 40 [ Time Frame: Baseline, Week 40 ]

Secondary Outcome Measures :
  1. Proportion of Participants With a Mean RGI-C Global Score ≥ +2.0 (Substantial Healing) at Week 40 [ Time Frame: Baseline, Week 40 ]
  2. Proportion of Participants With a Mean RGI-C Global Score ≥ +2.0 (Substantial Healing) at Week 64 [ Time Frame: Baseline, Week 64 ]
  3. Change From Baseline in Rickets as Assessed by the RGI-C Global Score at Week 64 [ Time Frame: Baseline, Week 64 ]
  4. Change From Baseline in Rickets Severity Score (RSS) Total Score at Week 40 [ Time Frame: Baseline, Week 40 ]
  5. Change From Baseline in RSS Total Score at Week 64 [ Time Frame: Baseline, Week 64 ]
  6. Change in Lower Extremity Skeletal Abnormalities, Including Genu Varum and Genu Valgus, as Assessed by the RGI-C Long Leg Score at Week 40 [ Time Frame: Baseline, Week 40 ]
  7. Change in Lower Extremity Skeletal Abnormalities, Including Genu Varum and Genu Valgus, as Assessed by the RGI-C Long Leg Score at Week 64 [ Time Frame: Baseline, Week 64 ]
  8. Change From Baseline in Standing Height (or Recumbent Length in Children < 2 Years) to Week 24 [ Time Frame: Baseline, Week 24 ]
  9. Change From Baseline in Standing Height (or Recumbent Length in Children < 2 Years) to Week 40 [ Time Frame: Baseline, Week 40 ]
  10. Change From Baseline in Standing Height (or Recumbent Length in Children < 2 Years) to Week 64 [ Time Frame: Baseline, Week 64 ]
  11. Change From Baseline in Height-For-Age Z-Scores to Week 24 [ Time Frame: Baseline, Week 24 ]
  12. Change From Baseline in Height-For-Age Z-Scores to Week 40 [ Time Frame: Baseline, Week 40 ]
  13. Change From Baseline in Height-For-Age Z-Scores to Week 64 [ Time Frame: Baseline, Week 64 ]
  14. Change in Growth Velocity From Pre-Treatment and Post-Treatment at Week 40 [ Time Frame: Baseline, Week 40 ]
  15. Change in Growth Velocity From Pre-Treatment and Post-Treatment at Week 64 [ Time Frame: Baseline, Week 64 ]
  16. Change From Baseline Over Time in Serum Phosphorus [ Time Frame: Baseline, up to Week 170 ]
  17. Change From Baseline Over Time in Serum 1,25(OH)D [ Time Frame: Baseline, up to Week 170 ]
  18. Change From Baseline Over Time in Urinary Phosphorus [ Time Frame: Baseline, up to Week 170 ]
  19. Change From Baseline Over Time in Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate (TmP/GFR) [ Time Frame: Baseline, up to Week 170 ]
  20. Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) [ Time Frame: Baseline, up to Week 170 ]
  21. Change From Baseline Over Time in Alkaline Phosphatase (ALP) [ Time Frame: Baseline, up to Week 170 ]
  22. Percent Change From Baseline Over Time in ALP [ Time Frame: Baseline, up to Week 170 ]
  23. Change From Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 24 [ Time Frame: Baseline, Week 24 ]
  24. Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 [ Time Frame: Baseline, Week 40 ]
  25. Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 [ Time Frame: Baseline, Week 64 ]
  26. Change From Baseline in the Faces Pain Scale-Revised (FPS-R) (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 24 [ Time Frame: Baseline, Week 24 ]
  27. Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 [ Time Frame: Baseline, Week 40 ]
  28. Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 [ Time Frame: Baseline, Week 64 ]
  29. Change From Baseline in the Six Minute Walk Test (6MWT) Total Distance (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 24 [ Time Frame: Baseline, Week 24 ]
  30. Change From Baseline in the 6MWT Total Distance (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 [ Time Frame: Baseline, Week 40 ]
  31. Change From Baseline in the 6MWT Total Distance (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 [ Time Frame: Baseline, Week 64 ]
  32. Percent of Predicted Normal in the 6MWT Total Distance (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 24 [ Time Frame: Week 24 ]
  33. Percent of Predicted Normal in the 6MWT Total Distance (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 [ Time Frame: Baseline, Week 40 ]
  34. Percent of Predicted Normal in the 6MWT Total Distance (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 [ Time Frame: Baseline, Week 64 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, aged 1 to ≤12 years with radiographic evidence of rickets as determined by central read
  2. PHEX mutation or variant of uncertain significance in either the patient or in a directly related family member with appropriate X-linked inheritance
  3. Biochemical findings associated with XLH: Serum phosphorus <3.0 mg/dL (<0.97 mmol/L)
  4. Serum creatinine below the age-adjusted upper limit of normal
  5. Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit
  6. Have received both oral phosphate and active vitamin D therapy for ≥ 12 consecutive months (for children ≥3 years of age) or ≥ 6 consecutive months (for children <3 years of age) 7 days prior to the Randomization Visit
  7. Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history.
  8. Provide written or verbal assent (as appropriate for the subject and region) 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. Female subjects of childbearing potential must be willing to use a highly effective method of contraception for the duration of the study plus 12 weeks after stopping the study drug. Sexually active male subjects with female partners of childbearing potential must consent to use a condom with spermicide or a highly effective method of contraception for the duration of the study plus 12 weeks after stopping the study drug.

Exclusion Criteria:

  1. Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, based on physical examination
  2. Height percentile > 50th based on country-specific norms
  3. Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit
  4. Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty
  5. Use of growth hormone therapy within 12 months before the Screening Visit
  6. Presence of nephrocalcinosis on renal ultrasound grade 4
  7. Planned orthopedic surgery, including osteotomy or implantation or removal of staples, 8 plates, or any other hardware, within the first 40 weeks of the study
  8. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
  9. Evidence of hyperparathyroidism (PTH levels 2.5X upper limit of normal [ULN])
  10. Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months prior to the Screening Visit
  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. History of recurrent infection or predisposition to infection, or of known immunodeficiency
  14. Use of a therapeutic monoclonal antibody within 90 days prior to the Screening Visit or history of allergic or anaphylactic reactions to any monoclonal antibody
  15. Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects.
  16. 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. OR, in Japan, use of any investigational product or investigational medical device within 4 months 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): NCT02915705


  Show 23 Study Locations
Sponsors and Collaborators
Ultragenyx Pharmaceutical Inc
Kyowa Hakko Kirin Co., Ltd
Investigators
Study Director: Medical Director Ultragenyx Pharmaceutical Inc

Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02915705     History of Changes
Other Study ID Numbers: UX023-CL301
First Posted: September 27, 2016    Key Record Dates
Last Update Posted: September 3, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Hypophosphatemia
Familial Hypophosphatemic Rickets
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
Vitamins
Vitamin D
Ergocalciferols
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents