Efficacy and Safety of Burosumab Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With XLH

NCT02915705 | Completed Phase 3 Results DMC

• 1 other identifier: UX023-CL301
• Study Type: interventional
• Target: 61
• Locations: 7 countries
• Sites: 16

Brief Summary

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

Conditions

X-Linked Hypophosphatemia

Outcome Measures

Primary Outcomes (1)

• Radiographic Global Impression of Change (RGI-C) Global Score at Week 40

  Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-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).

  Week 40

Secondary Outcomes (31)

• Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40

  Week 40

• Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64

  Week 64

• RGI-C Global Score at Week 64

  Week 64

• Change From Baseline in RSS Total Score at Week 40

  Baseline, Week 40

• Change From Baseline in RSS Total Score at Week 64

  Baseline, Week 64

Study Arms (2)

Burosumab

EXPERIMENTAL

Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.

Biological: burosumab

Active Control

ACTIVE COMPARATOR

Multiple daily doses of oral phosphate and one or more daily doses of active vitamin D therapy, titrated and individualized by the investigator based on published recommendations during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.

Biological: burosumab; Drug: Oral Phosphate Supplement; Drug: active vitamin D

Interventions

burosumab BIOLOGICAL

solution for subcutaneous (SC) injection

Also known as: KRN23, Crysvita ®, UX023

Active Control; Burosumab

Oral Phosphate Supplement DRUG

oral tablet; oral solution; oral powder

Active Control

active vitamin D DRUG

tablet, oral solution

Active Control

Eligibility Criteria

• Age: 1 Year - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female, aged 1 to ≤12 years with radiographic evidence of rickets as determined by central readers
• Phosphate-regulating endopeptidase homolog, X-linked (PHEX) mutation or variant of uncertain significance in either the patient or in a directly related family member with appropriate X-linked inheritance
• Biochemical findings associated with XLH: serum phosphorus \<3.0 mg/dL (\<0.97 mmol/L)
• Serum creatinine below the age-adjusted upper limit of normal
• Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit
• 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
• Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history
• 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.
• 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
• 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

You may not qualify if:

• Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, based on physical examination
• Height percentile \> 50th based on country-specific norms
• Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit
• Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty
• Use of growth hormone therapy within 12 months before the Screening Visit
• Presence of nephrocalcinosis on renal ultrasound grade 4
• 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
• Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
• Evidence of hyperparathyroidism (parathyroid hormone \[PTH\] levels 2.5X upper limit of normal \[ULN\])
• Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months prior to the Screening Visit
• 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.
• Presence of a concurrent disease or condition that would interfere with study participation or affect safety
• History of recurrent infection or predisposition to infection, or of known immunodeficiency
• 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
• 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

Sponsors & Collaborators

• Kyowa Kirin, Inc.: lead
• Kyowa Kirin Co., Ltd.: collaborator

Study Sites (16)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

UCSF

San Francisco, California, 94158, United States

Location

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

Location

Shriners Hospital For Children

St Louis, Missouri, 63110, United States

Location

Vanderbilt Children's Hospital

Nashville, Tennessee, 37232, United States

Location

The Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Children's Hospital of Eastern Ontario (CHEO) Research Institute

Ottawa, Ontario, K1H 8L1, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Shriners Hospital for Children - Canada

Montreal, Quebec, H4A 0A9, Canada

Location

Kanagawa Children's Medical Center

Yokohama, Kanagawa, 232-8555, Japan

Location

Okayama Saiseikai General Hospital

Okayama, 700-0013, Japan

Location

Japan Community Healthcare Organization Osaka Hospital

Osaka, 553-0003, Japan

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Karolinska Institutet and University Hospital

Stockholm, 17176, Sweden

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

Royal Manchester Children's Hospital - University of Manchester

Manchester, M13 9WL, United Kingdom

Location

Related Publications (5)

• Imel EA, Glorieux FH, Whyte MP, Portale AA, Munns CF, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Hogler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Chen A, Roberts MS, Ward LM. Burosumab vs Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Subgroup Analysis by Dose Level. J Clin Endocrinol Metab. 2023 Oct 18;108(11):2990-2998. doi: 10.1210/clinem/dgad230.

  PMID: 37084401 DERIVED

• Ward LM, Glorieux FH, Whyte MP, Munns CF, Portale AA, Hogler W, Simmons JH, Gottesman GS, Padidela R, Namba N, Cheong HI, Nilsson O, Mao M, Chen A, Skrinar A, Roberts MS, Imel EA. Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2022 Jul 14;107(8):e3241-e3253. doi: 10.1210/clinem/dgac296.

  PMID: 35533340 DERIVED

• Padidela R, Whyte MP, Glorieux FH, Munns CF, Ward LM, Nilsson O, Portale AA, Simmons JH, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Hogler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Williams A, Nixon A, Sun W, Chen A, Skrinar A, Imel EA. Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia. Calcif Tissue Int. 2021 May;108(5):622-633. doi: 10.1007/s00223-020-00797-x. Epub 2021 Jan 23.

  PMID: 33484279 DERIVED

• 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.

  PMID: 32721016 DERIVED

• Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Hogler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019 Jun 15;393(10189):2416-2427. doi: 10.1016/S0140-6736(19)30654-3. Epub 2019 May 16.

  PMID: 31104833 DERIVED

MeSH Terms

Conditions

Familial Hypophosphatemic Rickets

Interventions

burosumab

Condition Hierarchy (Ancestors)

Rickets, Hypophosphatemic; Rickets; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Hypophosphatemia, Familial; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Calcium Metabolism Disorders; Hypophosphatemia; Phosphorus Metabolism Disorders; Vitamin D Deficiency; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders

Results Point of Contact

• Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc

medinfo@ultragenyx.com

1-888-756-8567

Study Officials

• Medical Director

  Ultragenyx Pharmaceutical Inc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: May 23, 2016
• First Posted: September 27, 2016
• Study Start: September 8, 2016
• Primary Completion: February 12, 2018
• Study Completion: July 15, 2019
• Last Updated: August 29, 2024
• Results First Posted: April 11, 2019

Record last verified: 2024-08

Locations

US (5); CA (3); AU (1); KR (1); SE (1); JP (3); GB (2)