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      A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients

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          Abstract

          Efficacy of PA21 (sucroferric oxyhydroxide), a novel calcium-free polynuclear iron(III)-oxyhydroxide phosphate binder, was compared with that of sevelamer carbonate in an open-label, randomized, active-controlled phase III study. Seven hundred and seven hemo- and peritoneal dialysis patients with hyperphosphatemia received PA21 1.0–3.0 g per day and 348 received sevelamer 4.8–14.4 g per day for an 8-week dose titration, followed by 4 weeks without dose change, and then 12 weeks maintenance. Serum phosphorus reductions at week 12 were −0.71 mmol/l (PA21) and −0.79 mmol/l (sevelamer), demonstrating non-inferiority of, on average, three tablets of PA21 vs. eight of sevelamer. Efficacy was maintained to week 24. Non-adherence was 15.1% (PA21) vs. 21.3% (sevelamer). The percentage of patients that reported at least one treatment-emergent adverse event was 83.2% with PA21 and 76.1% with sevelamer. A higher proportion of patients withdrew owing to treatment-emergent adverse events with PA21 (15.7%) vs. sevelamer (6.6%). Mild, transient diarrhea, discolored feces, and hyperphosphatemia were more frequent with PA21; nausea and constipation were more frequent with sevelamer. After 24 weeks, 99 hemodialysis patients on PA21 were re-randomized into a 3-week superiority analysis of PA21 maintenance dose in 50 patients vs. low dose (250 mg per day (ineffective control)) in 49 patients. The PA21 maintenance dose was superior to the low dose in maintaining serum phosphorus control. Thus, PA21 was effective in lowering serum phosphorus in dialysis patients, with similar efficacy to sevelamer carbonate, a lower pill burden, and better adherence.

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          A systematic review of the prevalence and determinants of nonadherence to phosphate binding medication in patients with end-stage renal disease

          Background Cardiovascular events are the leading cause of death in end stage renal disease (ESRD). Adherence to phosphate binding medication plays a vital role in reducing serum phosphorus and associated cardiovascular risk. This poses a challenge for patients as the regimen is often complex and there may be no noticeable impact of adherence on symptoms. There is a need to establish the level of nonadherence to phosphate binding medication in renal dialysis patients and identify the factors associated with it. Methods The online databases PsycINFO, Medline, Embase and CINAHL were searched for quantitative studies exploring predictors of nonadherence to phosphate binding medication in ESRD. Rates and predictors of nonadherence were extracted from the papers. Results Thirty four studies met the inclusion criteria. There was wide variation in reported rates of non-adherence (22–74% patients nonadherent, mean 51%). This can be partially attributed to differences in the way adherence has been defined and measured. Demographic and clinical predictors of nonadherence were most frequently assessed but only younger age was consistently associated with nonadherence. In contrast psychosocial variables (e.g. patients' beliefs about medication, social support, personality characteristics) were less frequently assessed but were more likely to be associated with nonadherence. Conclusion Nonadherence to phosphate binding medication appears to be prevalent in ESRD. Several potentially modifiable psychosocial factors were identified as predictors of nonadherence. There is a need for further, high-quality research to explore these factors in more detail, with the aim of informing the design of an intervention to facilitate adherence.
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            PA21: a novel phosphate binder for the treatment of hyperphosphatemia in chronic kidney disease.

             P Geisser,  S Philipp (2010)
            Limitations of conventional phosphate binders have led to the development of novel non-calcium, non-aluminium agents for use in patients with chronic kidney disease (CKD). The iron-based agent PA21 (stabilized polynuclear iron(III)-oxyhydroxide) has high phosphate binding capacity in vitro. This study was undertaken to investigate the uptake of iron after oral administration of PA21 in order to identify any potential risk of iron overload in the clinical setting, and to obtain a preliminary assessment of the effect of PA21 on serum phosphate levels prior to larger trials over a longer treatment period. An open-label, Phase I study was undertaken in which PA21 10 g/day was administered for 7 days to 8 nondialysis-dependent CKD patients (Stages 3 - 4), 8 maintenance hemodialysis patients and 8 healthy subjects. In addition, a single dose of radiolabeled PA21 was administered to determine iron uptake. Median iron uptake (range) was 0.06% (0.008 - 0.44%), 0.02% (0 - 0.04%) and 0.43% (0.16% - 1.25%) in the nondialysis-dependent CKD patients, hemodialysis patients and healthy subjects, respectively. Serum phosphate level decreased over the 7-day treatment period in the nondialysis patients (1.44 + or - 0.29 mmol/l to 1.10 + or - 0.27 mmol/l, p < 0.01) and the hemodialysis patients (2.85 + or - 0.78 mmol/l to 2.25 + or - 0.85 mmol/, p < 0.01). The most common adverse event was diarrhea (n = 9); all cases were mild to moderate. Findings from this short-term study indicate that PA21 may be an efficacious and well-tolerated phosphate binder with low iron uptake that may offer a promising alternative to existing hyperphosphatemia therapies. These results will need to be confirmed with longer-term, controlled studies.
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              Phosphate – The Silent Stealthy Cardiorenal Culprit in All Stages of Chronic Kidney Disease

              Background and Aim: Due to increasing evidence suggesting a link between hyperphosphatemia and cardiovascular disease (CVD), mediated through vascular calcification in patients on dialysis, the following question arises: At what stage of chronic kidney disease (CKD) does the relationship between elevated phosphate levels, vascular calcification and increased cardiovascular mortality begin? Therefore, the purpose of the current study was to critically review the current literature regarding this issue. Methods: We performed a systematic search of the National Library of Medicine and the Cochrane Library databases from January 1985 to February 2008 to identify clinical studies examining the effects of plasma phosphate on cardiovascular outcome, mortality and progression of kidney disease in subjects with and without CKD who have not yet received dialysis. The primary outcome measure was the development of CVD, mortality and progression of kidney disease. Results: Twelve clinical trials investigated the role of serum phosphate levels and adverse outcome (9 studies examining CVD outcome and 3 examining progression of kidney disease). After adjustment for risk factors for mortality, adverse cardiovascular outcome and progression of kidney disease, all studies found a graded independent significant association between phosphate levels and mortality, development of CVD and progression of kidney disease. There was no such association with plasma calcium levels. Conclusions: There is a graded independent association between serum phosphate levels and mortality, mainly cardiovascular events, and the progression of renal disease in subjects with and without definable (loss of glomerular filtration rate) CKD.
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                Author and article information

                Journal
                Kidney Int
                Kidney Int
                Kidney International
                Nature Publishing Group
                0085-2538
                1523-1755
                September 2014
                19 March 2014
                : 86
                : 3
                : 638-647
                Affiliations
                [1 ]Division of Nephrology, RWTH University Hospital Aachen , Aachen, Germany
                [2 ]‘Grigore T Popa' University of Medicine and Pharmacy , Iasi, Romania
                [3 ]Coburg Clinic and KfH-Dialysis Center , Coburg, Germany
                [4 ]University of California , Los Angeles, California, USA
                [5 ]Vifor Pharma , Glattbrugg, Switzerland
                [6 ]NorthShore University Health System University of Chicago Pritzker School of Medicine , Evanston, Illinois, USA
                Author notes
                [* ]Division of Nephrology, RWTH University Hospital Aachen , 52057 Aachen, Germany. E-mail: juergen.floege@ 123456rwth-aachen.de
                Article
                ki201458
                10.1038/ki.2014.58
                4150998
                24646861
                Copyright © 2014 International Society of Nephrology

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                Categories
                Clinical Trial

                Nephrology

                dialysis, adherence, hyperphosphatemia, phosphate binder, pa21, sevelamer

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