Clinical trial NCT02915705: Efficacy and Safety of Burosumab Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With XLH
Official title: A Randomized, Open-Label, Phase 3 Study to Assess the Efficacy and Safety of KRN23 Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With X Linked Hypophosphatemia (XLH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: X-Linked Hypophosphatemia
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Kyowa Kirin Co., Ltd.
First posted: 2016-09-27
Enrollment: 61
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: Inclusion Criteria:

1. Male or female, aged 1 to ≤12 years with radiographic evidence of rickets as determined by central readers
2. 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
3. Biochemical findings associated with XLH: serum phosphorus \<3.0 mg/dL (\<0.97 mmol/L)
4. Serum creatinine below the age-adjusted upper limit of normal
5. Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit
6. 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
7. Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history
8. 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.
9. 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
10. 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

Exclusion Criteria:

1. Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, based on physical examination
2. Height percentile \> 50th based on country-specific norms
3. Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit
4. Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty
5. Use of growth hormone therapy within 12 months before the Screening Visit
6. Presence of nephrocalcinosis on renal ultrasound grade 4
7. 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
8. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
9. Evidence of hyperparathyroidism (parathyroid hormone \[PTH\] levels 2.5X upper limit of normal \[ULN\])
10. Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months prior to the Screening Visit
11. 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.
12. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
13. History of recurrent infection or predisposition to infection, or of known immunodeficiency
14. 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
15. 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
16. 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. 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

Primary outcomes:
measure: Radiographic Global Impression of Change (RGI-C) Global Score at Week 40
timeFrame: Week 40
Secondary outcomes:
measure: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40
timeFrame: Week 40
measure: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64
timeFrame: Week 64
measure: RGI-C Global Score at Week 64
timeFrame: Week 64
measure: Change From Baseline in RSS Total Score at Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in RSS Total Score at Week 64
timeFrame: Baseline, Week 64
measure: RGI-C Long Leg Score at Week 40
timeFrame: Week 40
measure: RGI-C Long Leg Score at Week 64
timeFrame: Week 64
measure: Change From Baseline in Height-For-Age Z-Scores to Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in Height-For-Age Z-Scores to Week 64
timeFrame: Baseline, Week 64
measure: Change in Growth Velocity Z Score From Baseline to Week 40
timeFrame: Baseline, Week 40
measure: Change in Growth Velocity Z Score From Baseline to Week 64
timeFrame: Baseline, Week 64
measure: Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64
timeFrame: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
measure: Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112
timeFrame: Baseline, Weeks 66, 68, 76, 88, 100, 112
measure: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64
timeFrame: Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64
measure: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)
timeFrame: Burosumab arm: Baseline, Week 1, 4, 8, 16, 24, 32, 40, 52, 64, 66, 68, 76, 88, 100, 112, 124, 140; Active Control arm: Baseline, Week 68, 76, 88, 100, 112, 124, 140
measure: Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)
timeFrame: Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140
measure: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64
timeFrame: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
measure: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112
timeFrame: Baseline, Weeks 68, 76, 88, 100, 112
measure: Change From Baseline Over Time in TmP/GFR, up to Week 64
timeFrame: Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64
measure: Change From Baseline Over Time in TmP/GFR, Week 68 to 112
timeFrame: Baseline, Weeks 68, 76, 88, 112
measure: Change From Baseline Over Time in Serum ALP, up to Week 64
timeFrame: Baseline, Weeks 16, 24, 40, 52, 64
measure: Change From Baseline Over Time in Serum ALP, Week 68 to 112
timeFrame: Baseline, Weeks 68, 76, 88, 100, 112
measure: Percent Change From Baseline Over Time in Serum ALP, up to Week 112
timeFrame: Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112
measure: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64
timeFrame: Baseline, Week 64
measure: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64
timeFrame: Baseline, Week 64
measure: Change From Baseline in the 6MWT Total Distance at Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in the 6MWT Total Distance at Week 64
timeFrame: Baseline, Week 64
measure: Percent of Predicted Normal in the 6MWT Total Distance at Week 40
timeFrame: Baseline, Week 40
measure: Percent of Predicted Normal in the 6MWT Total Distance at Week 64
timeFrame: Baseline, Week 64
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
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
city: Nashville
country: United States
facility: Vanderbilt Children's Hospital
state: Tennessee
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario (CHEO) Research Institute
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Shriners Hospital for Children - Canada
state: Quebec
city: Yokohama
country: Japan
facility: Kanagawa Children's Medical Center
state: Kanagawa
city: Okayama
country: Japan
facility: Okayama Saiseikai General Hospital
city: Osaka
country: Japan
facility: Japan Community Healthcare Organization Osaka Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Stockholm
country: Sweden
facility: Karolinska Institutet and University Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital - University of Manchester
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
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: 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.