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- Imel, Erik A., et al.
(författare)
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Burosumab versus conventional therapy in children with X-linked hypophosphataemia : a randomised, active-controlled, open-label, phase 3 trial
- 2019
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 393:10189, s. 2416-2427
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Tidskriftsartikel (refereegranskat)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 endopep-tidase 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
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- Nilsson, Ola, 1970-, et al.
(författare)
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Burosumab Improved Rickets, Phosphate Metabolism, and Clinical Outcomes Compared to Conventional Therapy in Children with X-Linked Hypophosphatemia (XLH) - A Randomized Controlled Phase 3 Study
- 2018
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 90:Suppl.1, s. 57-58
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In children with XLH, high circulating levels of FGF23 cause hypophosphatemia with consequent rickets, skeletal deformities, and growth impairment. Conventional therapy consists of multiple daily doses of oral phosphate and active vitamin D (Pi/D). Burosumab is a fully human monoclonal antibody against FGF23 indicated for the treatment of XLH.In the active-control study CL301 (NCT02915705), 61 children with XLH (1-12 years old) were randomized (1:1) to receive subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks (Q2W) or Pi/D as prescribed by investigators. Eligibility criteria included a Total Rickets Severity Score (RSS) ≥2.0 and prior receipt of Pi/D. The primary endpoint was healing of rickets at Week 40 assessed by radiologists blinded to treatment using the Radiographic Global Impression of Change (RGI-C).At Week 40, burosumab significantly improved rickets compared with Pi/D (RGI-C global score least squares [LS] mean ± SE: +1.92 ± 0.11 vs +0.77 ± 0.11; p<0.0001). More subjects in the burosumab group had substantial healing (RGI-C ≥+2.0) at Week 40, compared with the Pi/D group (21/29, 72% vs 2/32, 6%; odds ratio of 39.1, p<0.0001). Additional evidence for improvement of rickets included decreased Total RSS (LS mean ± SE change, burosumab vs Pi/D: -2.04 ± 0.145 vs -0.71 ± 0.138; p<0.0001), decreased alkaline phosphatase (-131 ± 13 vs -35 ± 19; p<0.0001), and improved RGI-C lower limb deformity score (+0.62 ± 0.12 vs +0.21 ± 0.12; p=0.020). At Week 40, increases in serum phosphorous (p<0.0001) and TmP/GFR (p<0.0001) were significantly greater with burosumab compared with Pi/D. Standing height Z-score increased in both treatment groups from baseline to Week 40 with an LS mean change of +0.15 (95% CI: 0.05, 0.25) for burosumab and +0.08 (-0.02, 0.19) for Pi/D. Percent predicted distance walked in six minutes increased with burosumab (Baseline to Week 40: 62% to 72%) and was unchanged with Pi/D (76% to 75%). Pre-defined adverse events (AEs) of interest, including hypersensitivity and injection site reaction, were higher in the burosumab group, but were mild to moderate in severity overall, with no discontinuations. There were 4 serious AEs (3 burosumab, 1 Pi/D); none were treatment-related and all resolved.In this randomized Phase 3 clinical trial, burosumab Q2W re-sulted in significantly greater improvements in rickets and phosphate metabolism compared with conventional therapy in 1-12 year-old children with XLH.
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