Clinical trial NCT02750618: Study of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: X-Linked Hypophosphatemia
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2016-04-25
Enrollment: 13
Sex: ALL
Minimum age (years): 1
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: Change From Baseline at Week 40 in Serum Phosphorus
timeFrame: Baseline, Week 40
measure: Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
timeFrame: From first dose of study drug through the end of the study (Week 160). Maximum duration of exposure to study drug was 160 weeks.
Secondary outcomes:
measure: Radiographic Global Impression of Change (RGI-C) Score at Week 40
timeFrame: Week 40
measure: RGI-C Score at Week 64
timeFrame: Week 64
measure: Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score
timeFrame: Baseline, Week 40
measure: Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score
timeFrame: Baseline, Week 64
measure: RGI-C Lower Limb Deformity Score at Week 40
timeFrame: Week 40
measure: RGI-C Lower Limb Deformity Score at Week 64
timeFrame: Week 64
measure: Change From Baseline Over Time in Recumbent Length/Standing Height
timeFrame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
measure: Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores
timeFrame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
measure: Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles
timeFrame: Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
measure: Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)
timeFrame: Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160
measure: Percent Change From Baseline Over Time in Serum ALP
timeFrame: Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Saint Louis
country: United States
facility: Shriners Hospital for Children
state: Missouri
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References:
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: 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.