Study of KRN23 in Adults With X-linked Hypophosphatemia (XLH)

NCT02526160 | Completed Phase 3 Results DMC

• 2 other identifiers: UX023-CL3032014-005529-11
• Study Type: interventional
• Target: 134
• Locations: 7 countries
• Sites: 25

Brief Summary

The primary efficacy objective of this study is to establish the effect of burosumab treatment compared with placebo on increasing serum phosphorus levels in adults with XLH.

Conditions

X-linked Hypophosphatemia

Keywords

KRN23; Fibroblast growth factor 23 (FGF23); XLH; X-linked hypophosphatemia; burosumab; Crysvita

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24

  Baseline through Week 24

Secondary Outcomes (32)

• Change From Baseline to Week 24 in Brief Pain Inventory (BPI) Question 3 (Q3; Worst Pain in Past 24 Hours) Score

  Baseline, 24 weeks

• Change From Baseline to Week 24 in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Stiffness Score

  Baseline, 24 weeks

• Change From Baseline to Week 24 in the WOMAC Physical Function Score

  Baseline, 24 weeks

• Change From Baseline Over Time in BPI Worst Pain Score

  Baseline, Weeks 12, 24, 36, 48, 72, 96

• Change From Baseline Over Time in BPI Pain Severity Score

  Baseline, Weeks 12, 24, 36, 48, 72, 96

Study Arms (2)

Burosumab 1 mg/kg

EXPERIMENTAL

Burosumab 1 mg/kg administered subcutaneously (SC) every 4 weeks, for the duration of the study.

Biological: burosumab

Placebo

PLACEBO COMPARATOR

Placebo administered SC every 4 weeks through Week 24, followed by burosumab 1 mg/kg, for the duration of the study.

Biological: burosumab; Other: Placebo

Interventions

burosumab BIOLOGICAL

solution for SC injection

Also known as: UX023, KRN23, Crysvita

Burosumab 1 mg/kg; Placebo

Placebo OTHER

saline solution for SC injection

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, aged 18 - 65 years, inclusive
• Diagnosis of XLH supported by classic clinical features of adult XLH (such as short stature or bowed legs) and at least ONE of the following at Screening:
• Documented phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance
• Serum intact FGF23 (iFGF23) level \> 30 pg/mL by Kainos assay
• Biochemical findings consistent with XLH at Screening Visit 2 following overnight fasting (min. 8 hours):
• Serum phosphorus \< 2.5 mg/dL
• TmP/GFR of \< 2.5 mg/dL
• Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of ≥ 4 on Brief Pain Inventory (BPI) Questions 3 (Worst Pain) at Screening Visit 1. (Skeletal pain that, in the opinion of the investigator, is attributed solely to causes other than XLH/osteomalacia-for example, back or joint pain in the presence of severe osteoarthritis by radiograph in that anatomical location-in the absence of any skeletal pain likely attributed to XLH/osteomalacia should not be considered for eligibility)
• Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation) or eGFR of 45 60 mL/min at Screening Visit 2 with confirmation that the renal insufficiency is not due to nephrocalcinosis
• If taking chronic pain medications (including narcotic pain medications/opioids), must be on a stable regimen for at least 21 days prior to Screening Visit 1, and be willing to maintain medications at the same stable dose(s) and schedule throughout the Placebo-controlled Treatment Period of the study. The dose must not exceed 60 mg oral morphine equivalents/day
• Provide written informed consent or if a minor, provide written consent and have a legally authorized representative willing and able to provide written informed consent, after the nature of the study has been explained, and prior to any research-related procedures
• Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history
• Females of child-bearing potential must have a negative urine pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have been in menopause for at least two years prior to Screening, or have had tubal ligation at least one year prior to Screening, or have had a total hysterectomy or bilateral salpingo-oophorectomy
• Participants of child-bearing potential or with partners of child-bearing potential who have not undergone a bilateral salpingo-oophorectomy and are sexually active must consent to use an effective method of contraception as determined by the site investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period following the signing of the informed consent through 12 weeks after last dose of study drug
• 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

You may not qualify if:

• Use of a pharmacologic vitamin D metabolite or analog (calcitriol, doxercalciferol, and paricalcitol) within 14 days prior to Screening Visit 2
• Use of oral phosphate within 14 days prior to Screening Visit 2
• Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening Visit 2
• Chronic use of systemic corticosteroids defined as more than 10 days in the previous 2 months
• Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening Visit 2
• Serum intact parathyroid hormone (iPTH) ≥ 2.5 upper limit of normal (ULN) at Screening Visit 1
• Use of medication to suppress parathyroid hormone (PTH) (cinacalcet for example) within 60 days prior to Screening Visit 1
• Use of oral bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1
• Use of denosumab in the 6 months prior to Screening Visit 1
• Use of teriparatide in the 2 months prior to Screening Visit 1
• Planned or recommended orthopedic surgery within the first 24 weeks of the clinical trial period
• History of traumatic fracture or orthopedic surgery within 6 months prior to Screening Visit 1
• Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening Visit 1
• Use of any investigational product or investigational medical device within 30 days prior to Screening Visit 1, 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.

Sponsors & Collaborators

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

Study Sites (25)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

University of California-San Francisco Medical Center

San Francisco, California, 94158, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

Location

Indiana University Department of Medicine

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21224, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43203, United States

Location

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

CHU de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction

Le Kremlin-Bicêtre, 94275, France

Location

Hôpital Lariboisière, Dept. of Rheumatology

Paris, 75010, France

Location

CHU Paris Centre-Hôpital Cochin

Paris, 75014, France

Location

St. Vincent's University Hospital

Dublin, 4, Ireland

Location

Azienda Ospedaliero Universitaria Careggi - Neurofarba

Florence, 50139, Italy

Location

Okayama Saiseikai General Hospital

Okayama, 700-0013, Japan

Location

Osaka City University Hospital

Osaka, 545-8586, Japan

Location

Osaka University Hospital

Osaka, 565-0871, Japan

Location

Toranomon Hospital

Tokyo, 105-8470, Japan

Location

The University of Tokyo Hospital

Tokyo, 113-8655, Japan

Location

Seoul National University Hospital

Seoul, 110-744, South Korea

Location

Asan Medical Center

Seoul, 138-736, South Korea

Location

University of Edinburgh Edinburgh Clinical Trials Unit (ECTU) - Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

Location

Univeristy College of London Hospital

London, WC1C 3BG, United Kingdom

Location

University of Oxford

Oxford, OX3 7HE, United Kingdom

Location

Northern General Hospital, Metabolic Bone Centre (Sorby Wing)

Sheffield, S5 7AU, United Kingdom

Location

Royal National Orthopaedic Hospital

Stanmore, HA7 4LP, United Kingdom

Location

Related Publications (5)

• Insogna KL, Briot K, Imel EA, Kamenicky P, Ruppe MD, Portale AA, Weber T, Pitukcheewanont P, Cheong HI, Jan de Beur S, Imanishi Y, Ito N, Lachmann RH, Tanaka H, Perwad F, Zhang L, Chen CY, Theodore-Oklota C, Mealiffe M, San Martin J, Carpenter TO; AXLES 1 Investigators. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res. 2018 Aug;33(8):1383-1393. doi: 10.1002/jbmr.3475. Epub 2018 Jun 26.

  PMID: 29947083 RESULT

• Portale AA, Carpenter TO, Brandi ML, Briot K, Cheong HI, Cohen-Solal M, Crowley R, Jan De Beur S, Eastell R, Imanishi Y, Imel EA, Ing S, Ito N, Javaid M, Kamenicky P, Keen R, Kubota T, Lachmann R, Perwad F, Pitukcheewanont P, Ralston SH, Takeuchi Y, Tanaka H, Weber TJ, Yoo HW, Zhang L, Theodore-Oklota C, Mealiffe M, San Martin J, Insogna K. Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period. Calcif Tissue Int. 2019 Sep;105(3):271-284. doi: 10.1007/s00223-019-00568-3. Epub 2019 Jun 4.

  PMID: 31165191 RESULT

• Kamenicky P, Briot K, Brandi ML, Cohen-Solal M, Crowley RK, Keen R, Kolta S, Lachmann RH, Lecoq AL, Ralston SH, Walsh JS, Rylands AJ, Williams A, Sun W, Nixon A, Nixon M, Javaid MK. Benefit of burosumab in adults with X-linked hypophosphataemia (XLH) is maintained with long-term treatment. RMD Open. 2023 Feb;9(1):e002676. doi: 10.1136/rmdopen-2022-002676.

  PMID: 36854566 DERIVED

• Brandi ML, Jan de Beur S, Briot K, Carpenter T, Cheong HI, Cohen-Solal M, Crowley RK, Eastell R, Imanishi Y, Imel EA, Ing SW, Insogna K, Ito N, Javaid K, Kamenicky P, Keen R, Kubota T, Lachmann RH, Perwad F, Pitukcheewanont P, Portale A, Ralston SH, Tanaka H, Weber TJ, Yoo HW, Sun W, Williams A, Nixon A, Takeuchi Y. Efficacy of Burosumab in Adults with X-linked Hypophosphatemia (XLH): A Post Hoc Subgroup Analysis of a Randomized Double-Blind Placebo-Controlled Phase 3 Study. Calcif Tissue Int. 2022 Oct;111(4):409-418. doi: 10.1007/s00223-022-01006-7. Epub 2022 Aug 4.

  PMID: 35927518 DERIVED

• Briot K, Portale AA, Brandi ML, Carpenter TO, Cheong HI, Cohen-Solal M, Crowley RK, Eastell R, Imanishi Y, Ing S, Insogna K, Ito N, Jan de Beur S, Javaid MK, Kamenicky P, Keen R, Kubota T, Lachmann RH, Perwad F, Pitukcheewanont P, Ralston SH, Takeuchi Y, Tanaka H, Weber TJ, Yoo HW, Nixon A, Nixon M, Sun W, Williams A, Imel EA. Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension. RMD Open. 2021 Sep;7(3):e001714. doi: 10.1136/rmdopen-2021-001714.

  PMID: 34548383 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

1-888-756-8657

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: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: July 17, 2015
• First Posted: August 18, 2015
• Study Start: October 22, 2015
• Primary Completion: December 22, 2016
• Study Completion: December 6, 2018
• Last Updated: June 18, 2024
• Results First Posted: February 5, 2021

Record last verified: 2024-06

Locations

FR (3); GB (5); US (8); IT (1); JP (5); IE (1); KR (2)