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

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 1.0–3.0g per day and 348 received sevelamer 4.8–14.4g 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 -0.71mmol/l (PA21) and -0.79mmol/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 (250mg 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. 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 1.0–3.0g per day and 348 received sevelamer 4.8–14.4g 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 -0.71mmol/l (PA21) and -0.79mmol/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 (250mg 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. Hyperphosphatemia is an almost inevitable consequence of chronic kidney disease, particularly in its advanced stages. In chronic kidney disease patients, the inability to maintain phosphorus balance is central to the development of chronic kidney disease-mineral and bone disorder1.Hruska K.A. Mathew S. The roles of the skeleton and phosphorus in the CKD mineral bone disorder.Adv Chronic Kidney Dis. 2011; 18: 98-104Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar and is associated with increased cardiovascular events2.Block G.A. Control of serum phosphorus: implications for coronary artery calcification and calcific uremic arteriolopathy (calciphylaxis).Curr Opin Nephrol Hypertens. 2001; 10: 741-747Crossref PubMed Scopus (67) Google Scholar and increased mortality.3.Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2208) Google Scholar, 4.Palmer S.C. Hayen A. Macaskill P. et al.Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis.JAMA. 2011; 305: 1119-1127Crossref PubMed Scopus (533) Google Scholar, 5.Kanbay M. Goldsmith D. Akcay A. et al.Phosphate—the silent stealthy cardiorenal culprit in all stages of chronic kidney disease: a systematic review.Blood Purif. 2009; 27: 220-230Crossref PubMed Scopus (64) Google Scholar Most patients on dialysis require phosphate binders to control hyperphosphatemia. Treatment with phosphate binders has been associated with a survival benefit.7.Isakova T. Gutierrez O.M. Chang Y. et al.Phosphorus binders and survival on hemodialysis.J Am Soc Nephrol. 2009; 20: 388-396Crossref PubMed Scopus (309) Google Scholar,8.Lopes A.A. Tong L. Thumma J. et al.Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): Evaluation of Possible Confounding by Nutritional Status.Am J Kidney Dis. 2012; 60: 90-101Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar However, most phosphate binders are associated with a high pill burden, posing a major obstacle to adherence for patients attempting to maintain optimal control of serum phosphorus concentrations.9.Arenas M.D. Malek T. Gil M.T. et al.Challenge of phosphorus control in hemodialysis patients: a problem of adherence?.J Nephrol. 2010; 23: 525-534PubMed Google Scholar,10.Chiu Y.W. Teitelbaum I. Misra M. et al.Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (401) Google Scholar A phosphate binder with a low pill burden and good tolerability may improve adherence and could thereby help optimize serum phosphorus control in patients on dialysis.11.Wang S. Alfieri T. Braunhofer P. et al.Pill burden and its Association with Medication Possession Ratio Among Hemodialysis Patients with Hyperphosphatemia.Abstract presented at the European Renal Association—European Dialysis and Transplantation Association Annual Meeting. Paris, France2012: 24-27Google Scholar PA21 (sucroferric oxyhydroxide) is a new calcium-free polynuclear iron(III)-oxyhydroxide phosphate binder with a high phosphate binding capacity over a wide pH range.12.Geisser P. Philipp E. PA21: a novel phosphate binder for the treatment of hyperphosphatemia in chronic kidney disease.Clin Nephrol. 2010; 74: 4-11Crossref PubMed Google Scholar It is formulated as flavored, chewable tablets that disintegrate easily in the gastrointestinal (GI) tract, bind phosphate across the whole physiologically relevant pH range, each contain 500mg of iron, and may be taken without water. Phase I studies demonstrated that PA21 was well tolerated and that GI iron absorption was minimal.12.Geisser P. Philipp E. PA21: a novel phosphate binder for the treatment of hyperphosphatemia in chronic kidney disease.Clin Nephrol. 2010; 74: 4-11Crossref PubMed Google Scholar,13.Hergesell O. Ritz E. Stabilized polynuclear iron hydroxide is an efficient oral phosphate binder in uraemic patients.Nephrol Dial Transplant. 1999; 14: 863-867Crossref PubMed Scopus (72) Google Scholar A phase II dose-finding study demonstrated that PA21 doses of 1.0-2.5g per day (based on iron content) were well tolerated and significantly lowered serum phosphorus concentrations from baseline, with maximal effects observed at 2.0–2.5g per day (P<0.001). A low dose (LD) of PA21 (250mg per day) was found to be ineffective.14.Wuthrich R.P. Chonchol M. Covic A. et al.Randomized clinical trial of the iron-based phosphate binder PA21 in hemodialysis patients.Clin J Am Soc Nephrol. 2013; 8: 280-289Crossref PubMed Scopus (67) Google Scholar In this phase III study, the efficacy and safety of PA21 was compared with that of sevelamer carbonate (SEV) in treating hyperphosphatemia in patients undergoing dialysis (Figure 1). Overall, 1059 patients were randomized in this study. Of these, four did not receive treatment (Figure 2). Hence, 1055 patients were included in the safety set (SS). Of those 1055, 1041 patients were included in the full analysis set (FAS), defined as patients randomized to treatment who received at least one dose of study medication and had at least one postbaseline evaluable efficacy assessment. The per-protocol set (PPS; n=685) consisted of patients who, in addition to the FAS criteria, had completed the treatment from baseline to week 12 and had at least one evaluable serum phosphorus result at or after week 12, with no major protocol deviations. Patient disposition (stage 1) is shown in Figure 2. Reasons for patients failing screening were: entry criteria not met (other than serum phosphorus concentration; 39.1%), serum phosphorus concentration <1.94mmol/l (34.3%), withdrawal of consent (6.4%), investigator decision (1.8%), death during screening/washout (0.3%), and other (18.4%). Patient baseline demographics (stage 1) are given in Table 1. Treatment groups were largely similar with regard to baseline characteristics, with no major differences between demographic subgroups. Across both treatment groups, 92% of patients were undergoing HD.Table 1Baseline demographics, Stage 1 (FAS; N=1041)ParameterPA21SevelamerTotalN (%)694 (100%)347 (100%)1041 (100%)Mean (s.d.) age (years)56 (13)56 (15)56 (14)Male (%)55.263.157.8Race White (%)77.275.876.8 Black/African American (%)18.321.619.4 Other (s.d.) for disease Other Hemodialysis (s.d.) from dialysis phosphate binders in 12 Other full analysis in a new full analysis The most major protocol were to study treatment treatment weeks and use of phosphate binders during or use of phosphate binders between baseline and week 12 from baseline to week 24 was in the PA21 treatment and in the treatment that to study treatment as of the of was more in patients compared with PA21 vs. differences in between the PA21 and treatment groups were Overall, of patients PA21 and of those were from the study. The most for study withdrawal were adverse events other than phosphorus or calcium concentrations and consent (Figure 2). (s.d.) serum phosphorus concentrations in the FAS were in the PA21 and in the of PA21 was the of the of the in from baseline to week 12 in serum phosphorus was was the non-inferiority of and Table in serum phosphorus concentrations from baseline to week 12 were -0.71mmol/l in the PA21 and -0.79mmol/l in the of the non-inferiority analysis in the FAS were with the of the of the in from baseline to week 12 in serum phosphorus was was the non-inferiority were no of demographic and disease the of with treatment Patients PA21 and treatment on and tablets per in the baseline phosphorus were and (Figure reductions in serum phosphorus were in both treatment groups and were maintained to the week 24 (Figure the 12 weeks, pill burden in the PA21 and treatment groups was and tablets per The pill burden in the maintenance phase was tablets per day for PA21 and tablets per day for (Figure The pill burden with than with PA21 over the whole of the study, and the of tablets taken per day from baseline to week 24 for PA21 and for week serum phosphorus concentrations in the efficacy set were similar in both treatment in the maintenance dose and in the Figure In the serum phosphorus concentrations did not significantly from weeks 24 to However, in the increased by was significantly higher than that in the thereby demonstrating superiority of the were no of demographic and disease with treatment were for the efficacy per-protocol serum parathyroid concentrations significantly from baseline to week 24 in both treatment the was more in the PA21 for the of between Table serum concentrations of from baseline to week 24 in both treatment groups and Table from baseline to week 24 was in both treatment groups, with the more with for the of between serum concentrations of from baseline to week 24 in the PA21 significantly from baseline to week 24 in the for the of between The percentage of patients that reported at least one treatment-emergent was higher with PA21 than with reported more with PA21 were discolored and hyperphosphatemia constipation and nausea were reported more with over 24 weeks in 1 2). of and and were similar between PA21 and treatment and in of patients in treatment 1 to GI GI discolored safety treatment-emergent adverse in a new safety treatment-emergent adverse or were to study treatment by the investigator not with PA21 was for of discolored feces, was as per PA21 was not and the was reported as without in the PA21 treatment a with GI as and was were to study were to A higher of to withdrawal was observed with PA21 and for PA21 and In both treatment groups, GI events for of the to withdrawal and The most frequent to withdrawal are shown in Table Of of patients in the PA21 withdrew of hyperphosphatemia, compared with in the not over the of the study, of patients received and of patients dose for that to study withdrawal in of patients in treatment 1 adverse safety treatment-emergent in a new adverse safety treatment-emergent The most frequent were GI in The of GI was higher with PA21 vs. with Table 2). of discolored feces, the of GI was in the PA21 and in the A higher proportion of was reported in the PA21 vs. in the differences between treatment groups were largely by higher of discolored and of discolored associated with PA21 were reported during the phase and to withdrawal presented in treatment (Figure and without the for or treatment The of patients were higher during the phase compared with the maintenance phase for both PA21 vs. and vs. Most of were in both the PA21 and to withdrawal in of patients PA21 in the and in of those are shown in Figure were no in serum concentrations increased in both treatment in were with are shown by and Figure In the and of patients received iron and during the study. of patients in the PA21 and of patients in the received iron during 1. of iron by was in the in and in all in the study. serum concentrations of did not from baseline to week 24 in the PA21 and by in the for the of between and Table PA21 was found to be to as reductions in serum phosphorus concentrations were similar and over the 12 weeks of and maintained its over 24 weeks with a lower pill burden than In treatment for weeks with PA21 was superior to PA21 in maintaining serum phosphorus control after 24 weeks of and efficacy were demonstrating that PA21 is effective for the control of hyperphosphatemia in dialysis patients. Patients undergoing dialysis and a high pill burden, with one study a of tablets per day and dialysis patients tablets per Y.W. Teitelbaum I. Misra M. et al.Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (401) Google Scholar binders for of this with a pill burden of Y.W. Teitelbaum I. Misra M. et al.Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (401) Google Scholar pill burden has been associated with adherence to phosphate binders and lower quality of Y.W. Teitelbaum I. Misra M. et al.Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (401) Google Scholar Non-adherence to phosphate as high as in patients with Y.W. Teitelbaum I. Misra M. et al.Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (401) Google Scholar has been associated with A. et with phosphate binder is associated with high serum phosphorus and from the Am Soc Nephrol. 2012; 23: PubMed Google Scholar the of cardiovascular disease, and M.D. Malek T. Gil M.T. et al.Challenge of phosphorus control in hemodialysis patients: a problem of adherence?.J Nephrol. 2010; 23: 525-534PubMed Google J. J. et systematic review of the and of to phosphate binding medication in patients with Nephrol. PubMed Scopus Google D. et and of to hemodialysis J Google Scholar from the of a dialysis that phosphate binder pill burden is associated with medication adherence by the medication in is associated with phosphorus S. Alfieri T. et al.Pill and its Association with Medication Possession Ratio Among Hemodialysis Patients with Hyperphosphatemia.Abstract presented at the Annual of the European Renal Association—European Dialysis and Transplantation Paris, France2012: 24-27Google Scholar pill burden, maintaining may adherence of dialysis patients to phosphate binders and to other In the study, patients with on more tablets per day than those PA21 vs. to control of serum phosphorus concentrations over 24 effects been as major for adherence or of, phosphate T. S. Braunhofer P. et for phosphate binder by binder Am Soc Nephrol. 2012; 23: PubMed Scopus Google Scholar in this the of was high in both treatment groups, was higher with PA21 than with of or and was similar between The higher of with PA21 was largely to higher of GI particularly and discolored included as or was in to and did not require treatment in the PA21 treatment be in more than one in patients with disease on dialysis J. The of in disease: a systematic Chronic Kidney Dis. 14: Full Text Full Text PDF PubMed Scopus Google Scholar Of the reported GI and were more in patients with compared with those has been reported to be associated with and Scholar been reported with other iron-based phosphate R.P. Chonchol M. Covic A. et al.Randomized clinical trial of the iron-based phosphate binder PA21 in hemodialysis patients.Clin J Am Soc Nephrol. 2013; 8: 280-289Crossref PubMed Scopus (67) Google M. M. M. et safety and tolerability of as a phosphate binder in dialysis 2012; PubMed Scopus Google Scholar and with iron-based in in concentrations was observed in both treatment groups, and an in was observed in the PA21 and on treatment with no of for the in iron is the use of iron in the of the study particularly in patients from the who for of all randomized patients: the of the by the for and to an in iron use during the in this study was et Practice for dialysis J Kidney Dis. 2012; 60: Full Text Full Text PDF PubMed Scopus Google Scholar of iron by and of and Figure is of this The higher use of iron in the compared with in and across all other in the is associated with a higher baseline serum and in serum from baseline to week 24 compared with the other However, the in and in the PA21 treatment that be that a of iron be from be in with from a phase I study of in of a dose of of PA21 was associated with iron absorption in chronic kidney disease patients on dialysis P. Philipp E. PA21: a novel phosphate binder for the treatment of hyperphosphatemia in chronic kidney disease.Clin Nephrol. 2010; 74: 4-11Crossref PubMed Google Scholar A more on iron has been reported with iron-based phosphate binder, M. et and efficacy of to hyperphosphatemia in hemodialysis patients: a randomized J Kidney Dis. 2013; Full Text Full Text PDF PubMed Scopus Google M. M. M. et safety and tolerability of as a phosphate binder in dialysis 2012; PubMed Scopus Google Scholar the in the effects on iron between the may be to the between the with PA21 to iron and P. Philipp E. PA21: a novel phosphate binder for the treatment of hyperphosphatemia in chronic kidney disease.Clin Nephrol. 2010; 74: 4-11Crossref PubMed Google Scholar PA21 was as the control in was to be in a phase II R.P. Chonchol M. Covic A. et al.Randomized clinical trial of the iron-based phosphate binder PA21 in hemodialysis patients.Clin J Am Soc Nephrol. 2013; 8: 280-289Crossref PubMed Scopus (67) Google Scholar a of a dose with PA21 A of the study is its However, use of a study was not owing to the differences in and of between PA21 and as a result of the PA21 iron be to Treatment adherence was on the of the of tablets by is that this of has and be with The dose of PA21 was taken three patients who were more than per day and were PA21 had at least one without a phosphate In the use of as a dose was not and may for the of to hyperphosphatemia in the PA21 treatment that in 1 of the study. However, by weeks the of tablets in the PA21 was (Figure that most patients in the PA21 were a three this the study for a three be that of patients in this study had received treatment with during the 12 study a proportion of patients may been with and to the effects associated with may the and of in this treatment In PA21 had similar efficacy and tolerability to in dialysis patients, a lower pill PA21 may a new treatment for hemo- and peritoneal dialysis patients, with the for adherence. was a open-label, randomized, active-controlled study of PA21 compared with in across the and (Figure 1). were major efficacy to non-inferiority of PA21 and superiority of the PA21 Stage 1 to week in serum phosphorus from baseline in the PA21 and treatment the efficacy was to non-inferiority of PA21 at week Stage was an open-label, 3-week of PA21 control dose of per day) in patients with The efficacy in was to superiority of PA21 The protocol was by or and the study was in with the of the on for for and was with the European and the of for consent and of The study is as on the consent was were The screening in patients completed a week from phosphate Patients with serum phosphorus concentrations were then randomized to treatment an Patients were randomized in a to receive PA21 1.0–3.0g per day chewable tablets per day) or 4.8–14.4g per day tablets per of PA21 are on iron PA21 chewable tablets are tablets are and in Patients PA21 1 with a dose of per day chewable tablets per and those with a dose of per day tablets per The dose at the of the study across the treatment the dose of PA21 was taken was taken three the of the study, patients in the PA21 were to one PA21 with each of the of the were defined as the with the phosphorus The study an 8-week dose titration, during doses of each could be for efficacy or followed by 4 weeks during dose were for A maintenance during dose was for efficacy and The dose for PA21 was 500mg per day weeks per day per day the dose was per day weeks per day per day Patients in were randomized to receive the dose of PA21 that had been at the of 1 or PA21 (250mg per day) for weeks, with no dose that a on serum phosphorus concentrations and as as in with clinical was at central could be for the of serum phosphorus concentrations for dose patients had a of hyperphosphatemia and were with doses of phosphate binders for patients received maintenance three per week or for at least Patients were to serum phosphorus concentrations during the Patients were for the study presented with parathyroid concentrations at or was or Patients were had GI or or major GI or serum at Patients on with a of in the or in the 12 were Patients phosphate binders with serum calcium or patients with serum calcium at screening were or and oral iron were not Patients were serum phosphorus concentrations the safety of or the lower safety of or serum calcium concentrations Patients on had study for the weeks of and then 4 weeks week 24. Study were to with the dialysis of the of was completed that serum phosphorus was Patients on had study week for the weeks of and then 4 weeks week 24. study were on the day In both and patients, and were from screening consent to the of study hyperphosphatemia was defined as serum phosphorus as serum phosphorus and as serum calcium dose or Patients had to be were Treatment adherence was on the of the of tablets by patients: The efficacy was an analysis of the superiority of PA21 in maintaining the phosphorus lowering in patients undergoing by serum phosphorus from weeks 24 to (stage Figure 1). The efficacy was an analysis of the non-inferiority of PA21 compared with in lowering serum phosphorus in patients on by in serum phosphorus from baseline to week 12 (stage 1). The safety were and and from The study was by the non-inferiority between PA21 and with the a in serum phosphorus concentrations of in both treatment groups, with a of a of a non-inferiority of and a of A of per-protocol patients was for a of patients from the per-protocol a of patients was was then increased to patients to to for The for of the study was on the efficacy The of patients for this analysis was 50 per a in serum phosphorus concentrations of between groups, a of a of and a of The study The FAS patients randomized to treatment who received dose of study medication and had at least one evaluable efficacy assessment. The consisted of patients who, in addition to the FAS criteria, had completed the treatment from baseline to week 12, had at least one evaluable serum phosphorus result at or after week 12, and had no major protocol deviations. The all randomized patients who at least one dose of study The efficacy set patients who were randomized to received dose of study medication during and had evaluable postbaseline efficacy during 2. The efficacy per-protocol set patients who were randomized to and had no major protocol deviations. The non-inferiority efficacy analysis was on the and the FAS an analysis of and the of with the baseline serum phosphorus dialysis or and and other as The efficacy analysis was an analysis of with week 24 serum phosphorus concentration and as for the efficacy set and efficacy per-protocol of for the efficacy the In other as from for disease, of phosphate use of the non-inferiority analysis and the between and treatment were in The were at a of were to safety from the adherence, on the of tablets taken to the to be was Patients were as adherence was of the all on efficacy were at the The were or in demographic and adherence and in the were not for and are all of the study The from Table of serum and and concentrations at baseline and 24 safety Table of in serum phosphorus concentrations from baseline to 12 and FAS Figure iron at baseline and at by is to the of the at with with