Erik A Imel1, Francis H Glorieux2, Michael P Whyte3, Craig F Munns4, Leanne M Ward5, Ola Nilsson6, Jill H Simmons7, Raja Padidela8, Noriyuki Namba9, Hae Il Cheong10, Pisit Pitukcheewanont11, Etienne Sochett12, Wolfgang Högler13, Koji Muroya14, Hiroyuki Tanaka15, Gary S Gottesman3, Andrew Biggin16, Farzana Perwad17, Meng Mao18, Chao-Yin Chen18, Alison Skrinar18, Javier San Martin18, Anthony A Portale17. 1. Department of Medicine and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: eimel@iu.edu. 2. Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada. 3. Shriners Hospitals for Children - St Louis, St Louis, MO, USA. 4. The University of Sydney Children's Hospital Westmead Clinical School, The Children's Hospital at Westmead, Westmead, NSW, Australia; Department of Endocrinology, The Children's Hospital at Westmead, Westmead, NSW, Australia. 5. Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. 6. Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden. 7. Department of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA. 8. Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK. 9. Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization, Osaka, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan. 10. Seoul National University Children's Hospital, Seoul, Korea. 11. Center of Endocrinology, Diabetes and Metabolism, Children's Hospital of Los Angeles, Los Angeles, CA, USA. 12. Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada. 13. Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK. 14. Kanagawa Children's Medical Center, Yokohama, Japan. 15. Okayama Saiseikai General Hospital Outpatient Center, Okayama, Japan. 16. The University of Sydney Children's Hospital Westmead Clinical School, The Children's Hospital at Westmead, Westmead, NSW, Australia. 17. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. 18. Ultragenyx Pharmaceutical, Novato, CA, USA.
Abstract
BACKGROUND: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.
RCT Entities:
BACKGROUND:X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.
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