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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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| 2. |
- Zaniew, Marcin, et al.
(författare)
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Long-term renal outcome in children with OCRL mutations : Retrospective analysis of a large international cohort
- 2018
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 33:1, s. 85-94
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Tidskriftsartikel (refereegranskat)abstract
- Background. Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Methods. Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Results. Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. Conclusions. CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.
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