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

NCT ID: NCT02526160

Last Updated: 2024-06-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 134 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-22
• Study Completion Date: 2018-12-06

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Burosumab 1 mg/kg

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

Group Type: EXPERIMENTAL

burosumab

Intervention Type: BIOLOGICAL

solution for SC injection

Placebo

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

Group Type: PLACEBO_COMPARATOR

burosumab

Intervention Type: BIOLOGICAL

solution for SC injection

Placebo

Intervention Type: OTHER

saline solution for SC injection

Interventions

burosumab

solution for SC injection

Intervention Type: BIOLOGICAL

Placebo

saline solution for SC injection

Intervention Type: OTHER

Other Intervention Names

UX023; KRN23; Crysvita

Eligibility Criteria

Inclusion Criteria

1. Male or female, aged 18 - 65 years, inclusive

2. 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

3. 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

4. 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)

5. 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

6. 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

7. 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

8. Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history

9. 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

10. 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

11. 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

12. Must have completed at least 4 of 7 days of the patient diaries before the Baseline visit.

Exclusion Criteria

1. Use of a pharmacologic vitamin D metabolite or analog (calcitriol, doxercalciferol, and paricalcitol) within 14 days prior to Screening Visit 2

2. Use of oral phosphate within 14 days prior to Screening Visit 2

3. Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening Visit 2

4. Chronic use of systemic corticosteroids defined as more than 10 days in the previous 2 months

5. Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening Visit 2

6. Serum intact parathyroid hormone (iPTH) ≥ 2.5 upper limit of normal (ULN) at Screening Visit 1

7. Use of medication to suppress parathyroid hormone (PTH) (cinacalcet for example) within 60 days prior to Screening Visit 1

8. Use of oral bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1

9. Use of denosumab in the 6 months prior to Screening Visit 1

10. Use of teriparatide in the 2 months prior to Screening Visit 1

11. Planned or recommended orthopedic surgery within the first 24 weeks of the clinical trial period

12. History of traumatic fracture or orthopedic surgery within 6 months prior to Screening Visit 1

13. Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening Visit 1

14. 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.

15. Pregnant or breastfeeding at Screening /Baseline or planning to become pregnant (self or partner) at any time during the study

16. Unable or unwilling to withhold prohibited medications throughout the study

17. Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects.

18. Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody

19. History of recurrent infection or predisposition to infection, or of known immunodeficiency

20. Presence of malignant neoplasm (except basal cell carcinoma)

21. Presence of a concurrent disease or condition that would interfere with study participation or affect safety

22. 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kyowa Kirin Co., Ltd.

INDUSTRY

Sponsor Role: collaborator

Kyowa Kirin, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Ultragenyx Pharmaceutical Inc

Locations

Children's Hospital of Los Angeles

Los Angeles, California, United States

University of California-San Francisco Medical Center

San Francisco, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Indiana University Department of Medicine

Indianapolis, Indiana, United States

Johns Hopkins University

Baltimore, Maryland, United States

Duke University Medical Center

Durham, North Carolina, United States

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Houston Methodist Hospital

Houston, Texas, United States

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

Le Kremlin-Bicêtre, , France

Hôpital Lariboisière, Dept. of Rheumatology

Paris, , France

CHU Paris Centre-Hôpital Cochin

Paris, , France

St. Vincent's University Hospital

Dublin, , Ireland

Azienda Ospedaliero Universitaria Careggi - Neurofarba

Florence, , Italy

Okayama Saiseikai General Hospital

Okayama, , Japan

Osaka City University Hospital

Osaka, , Japan

Osaka University Hospital

Osaka, , Japan

Toranomon Hospital

Tokyo, , Japan

The University of Tokyo Hospital

Tokyo, , Japan

Seoul National University Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

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

Edinburgh, , United Kingdom

Univeristy College of London Hospital

London, , United Kingdom

University of Oxford

Oxford, , United Kingdom

Northern General Hospital, Metabolic Bone Centre (Sorby Wing)

Sheffield, , United Kingdom

Royal National Orthopaedic Hospital

Stanmore, , United Kingdom

Countries

United States; France; Ireland; Italy; Japan; South Korea; United Kingdom

References

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.

Reference Type: RESULT

PMID: 29947083 (View on PubMed)

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.

Reference Type: RESULT

PMID: 31165191 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36854566 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35927518 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34548383 (View on PubMed)

Other Identifiers

2014-005529-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

UX023-CL303

Identifier Type: -

Identifier Source: org_study_id