Clinical trial NCT02526160: Study of KRN23 in Adults With X-linked Hypophosphatemia (XLH)
Official title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study With Open-Label Extension to Assess the Efficacy and Safety of KRN23 in Adults With X-linked Hypophosphatemia (XLH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: X-linked Hypophosphatemia
Keywords: KRN23
Fibroblast growth factor 23 (FGF23)
XLH
X-linked hypophosphatemia
burosumab
Crysvita
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Kyowa Kirin Co., Ltd.
First posted: 2015-08-18
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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
timeFrame: Baseline through Week 24
Secondary outcomes:
measure: Change From Baseline to Week 24 in Brief Pain Inventory (BPI) Question 3 (Q3; Worst Pain in Past 24 Hours) Score
timeFrame: Baseline, 24 weeks
measure: Change From Baseline to Week 24 in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Stiffness Score
timeFrame: Baseline, 24 weeks
measure: Change From Baseline to Week 24 in the WOMAC Physical Function Score
timeFrame: Baseline, 24 weeks
measure: Change From Baseline Over Time in BPI Worst Pain Score
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in BPI Pain Severity Score
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in BPI Pain Interference Score
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in WOMAC Stiffness Score
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144
measure: Change From Baseline Over Time in WOMAC Physical Function Score
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144
measure: Change From Baseline Over Time in BFI Worst Fatigue Score
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in BFI Global Fatigue Score
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in Biochemical Marker of Bone Remodeling Procollagen Type 1 N-Propeptide (P1NP)
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Percent Change From Baseline Over Time in Biochemical Marker of Bone Remodeling P1NP
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in Biochemical Marker of Bone Remodeling Carboxy-Terminal Cross-Linked Telopeptide of Type I Collagen (CTx)
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Percent Change From Baseline Over Time in Biochemical Marker of Bone Remodeling CTx
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in Biochemical Marker of Bone Remodeling Bone-Specific Alkaline Phosphatase (BALP)
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Percent Change From Baseline Over Time in Biochemical Marker of Bone Remodeling BALP
timeFrame: Baseline, Weeks 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in Serum Phosphorus
timeFrame: Baseline, Weeks 1, 2, 4, 6, 10, 12, 14, 18, 20, 21, 22, 24, 26, 28, 34, 36, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
measure: Percent Change From Baseline Over Time in Serum Phosphorus
timeFrame: Baseline, Weeks 1, 2, 4, 6, 10, 12, 14, 18, 20, 21, 22, 24, 26, 28, 34, 36, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
measure: Change From Baseline Over Time in Serum 1,25(OH)2D
timeFrame: Baseline, Weeks 1, 2, 4, 20, 21, 22, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
measure: Percent Change From Baseline Over Time in Serum 1,25(OH)2D
timeFrame: Baseline, Weeks 1, 2, 4, 20, 21, 22, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
measure: Change From Baseline Over Time in 24-Hour Urinary Phosphorus
timeFrame: Baseline, Week 12, 24, 36, 48, 72, 96
measure: Percent Change From Baseline Over Time in 24-Hour Urinary Phosphorus
timeFrame: Baseline, Week 12, 24, 36, 48, 72, 96
measure: Change From Baseline Over Time in Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate (TmP/GFR)
timeFrame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
measure: Percent Change From Baseline Over Time in TmP/GFR
timeFrame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
measure: Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP)
timeFrame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
measure: Percent Change From Baseline Over Time in TRP
timeFrame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
measure: Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline through Week 24
measure: Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline through Week 24
measure: Percent Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline through Week 24
measure: Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline through Week 24
measure: Percent Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline through Week 24
measure: Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24
timeFrame: Baseline through Week 24
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California-San Francisco Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Indianapolis
country: United States
facility: Indiana University Department of Medicine
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Le Kremlin-Bicêtre
country: France
facility: CHU de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction
city: Paris
country: France
facility: Hôpital Lariboisière, Dept. of Rheumatology
city: Paris
country: France
facility: CHU Paris Centre-Hôpital Cochin
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi - Neurofarba
city: Okayama
country: Japan
facility: Okayama Saiseikai General Hospital
city: Osaka
country: Japan
facility: Osaka City University Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Tokyo
country: Japan
facility: Toranomon Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Edinburgh
country: United Kingdom
facility: University of Edinburgh Edinburgh Clinical Trials Unit (ECTU) - Western General Hospital
city: London
country: United Kingdom
facility: Univeristy College of London Hospital
city: Oxford
country: United Kingdom
facility: University of Oxford
city: Sheffield
country: United Kingdom
facility: Northern General Hospital, Metabolic Bone Centre (Sorby Wing)
city: Stanmore
country: United Kingdom
facility: Royal National Orthopaedic Hospital
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.