Sucroferric Oxyhydroxide As Part of Combination Phosphate Binder Therapy Among Hemodialysis Patients

Original Investigation

Sucroferric Oxyhydroxide as Part of Combination Phosphate Binder Therapy among Hemodialysis Patients

Donald A. Molony,1 Vidhya Parameswaran,2 Linda H. Ficociello,2 Claudy Mullon,2 and Robert J. Kossmann2

Abstract Background Combination therapy with multiple phosphate binders is prescribed to reduce elevated serum phosphorus (sP) concentrations among patients on maintenance hemodialysis. Sucroferric oxyhydroxide (SO), an iron-based phosphate binder, has demonstrated efﬁcacy at reducing sP while also being associated with a low pill burden. Whereas the effects of SO monotherapy have been well characterized in clinical trials and observational cohorts, little is known about the effects of SO-containing combination therapy.

Methods Patients on hemodialysis (N5234) at Fresenius Kidney Care (FKC) who received $120 days of uninterrupted phosphate binder combination therapy with SO were included in this retrospective study. Patient data were censored after SO discontinuation, end of care at FKC, or completion of 12 months of follow-up. Quarterly (Q) changes in phosphate binder pill burden, mean sP, and proportion of patients achieving National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI)–recommended sP levels (#5.5 mg/dl) were compared between baseline (2Q1) and follow-up (Q1–Q4).

Results Phosphate binder combination therapy with SO was associated with signiﬁcant increase in the proportion of patients with sP #5.5 mg/dl (from 19% at baseline to up to 40% at follow-up; P,0.001) and reduction in sP at all postbaseline time points (from 6.7 mg/dl to 6.2–6.3 mg/dl; P,0.001). Patients on calcium acetate (N554) and sevelamer (N594) who added SO therapy at follow-up resulted in a $250% increase in patients achieving sP #5.5 mg/dl (all P,0.001). Whereas mean phosphate binder pill burden increased with initiation of phosphate binder combination therapy with SO (15.8 pills/d at Q1 versus 12.3 pills/d at 2Q1), continued use of SO was associated with down-titration of non-SO phosphate binders such that, by Q4, mean total PB pill burden reduced to 12.3 pills/d.

Conclusions For patients on hemodialysis with uncontrolled hyperphosphatemia, combination therapy with SO may allow for sustained improvements in sP control without adversely affecting phosphate binder pill burden. KIDNEY360 1: 263–272, 2020. doi: https://doi.org/10.34067/KID.0000332019

Introduction Prospective observational data collected as part of CKD is associated with disturbances in phosphorus COSMOS (the Current management Of Secondary homeostasis. In early stages of disease, compensatory hyperparathyroidism: a Multicentre Observational mechanisms can maintain physiologic phosphorus lev- Study) support efforts to lower elevated sP concentra- els (1,2). Compensatory mechanisms include increases tions in patients on HD (11). In COSMOS, a survival in phosphatonins such as fibroblast growth factor-23 benefit was observed among patients on HD with that directly reduce renal phosphate reabsorption and elevated baseline sP levels (i.e., .5.2 mg/dl [mean, also result in reductions in active vitamin D; the latter 6.5 mg/dl]) who demonstrated reductions in sP con- reduces phosphorus absorption from the gastrointes- centrations during follow-up. Strategies to lower sP in tinal tract and tubular reabsorption of filtered phos- patients on HD include restriction of dietary phosphate phorus by the kidney (3,4). As kidney function declines while ensuring adequate intake of protein and avoid- and compensatory mechanisms—in particular renal ance of malnutrition (12,13), adjustments in the HD excretion of phosphorus—are significantly impaired, prescription (12,14), and pharmacotherapy with phos- overt hyperphosphatemia can develop and is often phate binders (PBs) to reduce intestinal phosphate evident in later stages of CKD (i.e., stages 4 and 5) absorption (2). (5). High serum phosphorus (sP) levels have been asso- National Kidney Foundation Kidney Disease Out- ciated with adverse outcomes in the setting of ESKD, comes Quality Initiative guidelines recommend mainte- including increased risk of cardiovascular events and nance of sP between 3.5 and 5.5 mg/dl in patients on reduced survival, particularly among populations on dialysis (15). Because of a lack of data from randomized hemodialysis (HD) (6–10). controlled trials, recommendations regarding specific

1Division of Renal Diseases and Hypertension, Center for Clinical Research and Evidence-Based Medicine, McGovern Medical School University of Texas, Houston, Texas; and 2Fresenius Medical Care Renal Therapies Group, Waltham, Massachusetts

Correspondence: Dr. Donald A. Molony, Division of Renal Diseases and Hypertension, McGovern Medical School University of Texas, 6431 Fannin Street, MSB 5.134, Houston, TX 77030. Email: [email protected] www.kidney360.org Vol 1 April, 2020 Copyright © 2020 by the American Society of Nephrology 263 264 KIDNEY360

clinical approaches are largely absent from the guidelines. efficacy of such dosing strategies have not been rigorously Observational studies, however, demonstrate that prescribed studied in clinical trials. Nonetheless, combination PB ther- PB therapy is associated with a survival benefitamongpatients apy is used in clinical practice and has been associated with on HD (16–18). Presently, more than three quarters of patients a survival benefit in COSMOS (18,33,34). This retrospective on HD in the United States are prescribed PBs, but .40% have analysis aimed to examine the effects of SO among patients sP levels .5.5 mg/dl (19,20), and approximately 17% have sP on HD when prescribed with other PBs for up to 1 year. concentrations .7.0 mg/dl (20). According to Sekar et al. (21), PB selection should be individualized to the needs of the patient and should con- Materials and Methods sider the patient’s metabolic profile (e.g., iron and calcium Study Design stores), safety, pill burden, and cost. Pill burden and its poten- This retrospective cohort study used de-identified data tial effect on adherence may be particularly relevant for extracted from the Fresenius pharmacy (FreseniusRx) data- patients on HD because of the high rates of polypharmacy base. All adult, in-center patients on HD prescribed SO in in this population (22,23). Sucroferric oxyhydroxide (SO) is an combination with other PB(s) for at least 120 days of therapy effective, iron-based PB approved for the control of sP in as part of routine care at Fresenius Kidney Care (FKC) patients with CKD on dialysis with demonstrated effectiveness facilities between April 1, 2014 and April 1, 2015 were at a lower pill burden in randomized controlled trials with SO included in this analysis (Figure 1). SO is an iron-based monotherapy (24–29). The effectiveness of SO monotherapy PB with a recommended starting dose of three pills per day has also been assessed in retrospective studies examining the (administered as one pill three times daily with meals) “real-world” effects of starting, or switching to, SO therapy indicated for the control of sP levels in patients with CKD (30–32). In these analyses, improvements in sP, reductions in on dialysis. pill burden, and improved adherence have been reported. Eligible non-SO PBs included calcium acetate, lanthanum Combination therapy with PBs is not currently addressed carbonate, sevelamer carbonate, and sevelamer hydrochlo- within evidence-based recommendations and the safety and ride. Calcium carbonate as a PB was not included because we

Adult, HD patients at FKC facilities who received ≥ 30 days of SO + non-SO PB prescriptions between April 1, 2014 - April 1, 2015 n = 456

Patients with ≥ 120 days of PB Patients with < 120 days of PB combination therapy (SO + non-SO PB) combination therapy (SO + non-SO PB) Study Cohort Excluded n = 234 n = 222

Discharged Switched from Completed follow-up Discontinued Switched from from FKC* or (SO + non-SO PB) through Q4 follow-up prior to Q4 (SO + non-SO PB) disenrolled to SO Completers Non-completers to non-SO PB(s) from FreseniusRx monotherapy n = 134 n = 100 n = 147 n = 49 n = 26

(SO + non-SO PB) Discharged from FKC* Non-SO PB Non-SO PB throughout or disenrolled monotherapy polytherapy follow-up from FreseniusRx n=95 n=52 n = 76 n = 33

Switched from Switched from (SO + non-SO PB) (SO + non-SO PB) to SO monotherapy to non-SO PB(s) n = 58 n = 67

Non-SO PB Non-SO PB monotherapy polytherapy n=61 n=6

Figure 1. | Patient dispositionﬂow chart detailing patients in the overall study cohort (n5234) with subgroups and patients excluded from the overall study cohort but included in sensitivity analyses (n5222). *Reasons for discharge from Fresenius Kidney Care (FKC) included transplantation, transfer to non-FKC facilities, withdrawal from dialysis, or death. FreseniusRx, Fresenius specialty pharmacy; HD, hemodialysis; PB, phosphate binder; Q, quarter; SO, sucroferric oxyhydroxide. KIDNEY360 1: 263–272, April, 2020 Combination Phosphate Binder Therapy with Sucroferric Oxyhydroxide, Molony et al. 265

were unable to track prescriptions as it is available over the and the ﬁrst 120 days of follow-up (months 11, 12, 13, and counter. Treatment periods were deﬁned quarterly (Q) as 14) were evaluated. baseline (2Q1; 3 months before SO prescription) and follow- Blood samples were drawn, generally on the same day of up (Q1 through Q4; up to 12 months of SO prescription; each week, using standardized methods at FKC facilities and Figure 2). Treatment data were censored if (1)patients analyzed at Spectra Laboratories (Rockleigh, New Jersey). All disenrolled from FreseniusRx, (2) SO therapy was discon- statistical analyses were carried out using SAS version 9.4 (SAS tinued, or (3) patients no longer received HD at FKC facili- Institute Inc., Raleigh, NC). This study was approved by the ties (e.g., post-transplantation, transfer to other facilities, or New England Institutional Review Board (Needham, MA). death).

Results Clinical Variables and Statistical Analysis Overall Study Cohort (N5234) Clinical and laboratory parameters of interest included Out of 456 adult, in-center patients on HD at FKC facilities prescribed PB pills per day (for SO and non-SO PBs); serum who received one or more prescriptions of SO in combina- levels of phosphorus, calcium, and albumin; intact para- tion with other PBs between April 1, 2014 and April 1, 2015; thyroid hormone (PTH); single-pool values of normalized 234 individuals met the study criteria and were included in protein catabolic rate and dialysis adequacy (i.e., Kt/V); the analysis (Figure 1). Patients had a mean age of 52 years and dose and use of active vitamin D and calcimimetic and had been receiving HD treatment for approximately therapies. Mean clinical variables were summarized using 4.6 years (Table 1). Before the initiation of SO, mean (SD) sP least-squared means and compared between baseline and was 6.7 (1.4) mg/dl (range, 3.43–11.13 mg/dl). The most follow-up using repeated-measures mixed effects linear common baseline PB was sevelamer carbonate, and approx- regression. Laboratory measures repeated over any quar- imately one quarter of patients were on combination PB ter were averaged to account for short-term measurement therapy at baseline (i.e., before starting SO). Table 2 details variability. The proportion of patients within the upper the PB therapies received by all patients at baseline and in limit of NFK-KDOQI–recommended sP (sP #5.5 mg/dl) combination with SO at follow-up. was compared between baseline and follow-up. Categorical Treatment with SO was associated with significant reduc- data were compared using the McNemar chi-squared and tions in sP at all postbaseline time points from baseline (Figure Cochran Q tests. 3,Table3).Thereweresignificant increases in the proportion Analyses were carried out for all patients and the sub- of individuals with an sP #5.5 mg/dl (19% at baseline to group of patients who added SO therapy to their baseline PB 33%–40% at follow-up; P,0.001). The total PB pill burden regimen to examine changes in sP and daily PB pill burden increased from 12.366.4 pills per day at 2Q1 to 15.865.7 pills overall and were stratified by baseline PB regimen. Two per day at Q1 (P,0.001) with the addition of SO treatment, but sensitivity analyses were conducted. The first addressed the the non-SO PB pill burden was down-titrated over time such effect of loss to follow-up on study results by examining that, by Q4, mean total PB pill burden was 12.365.1 pills per subgroups of patients who completed SO treatment through day (2Q1 versus Q4, P50.9). Mean non-SO PB pill burden was Q4 (completers) and patients who discontinued SO therapy reduced by approximately 19% from 12.366.4 pills per day at during follow-up (noncompleters). The second sensitivity 2Q1 to 10.064.9 pills per day at Q4 (P50.05). analysis was conducted to assess the degree of selection bias Small decreases in serum albumin (4.0 mg/dl at 2Q1, and introduced by the requirement of 120 days of prescription of 3.97, 3.97, 3.98, and 3.96 mg/dl at Q1, Q2, Q3, and Q4, SO in combination with other PBs. Patients on HD who respectively; P50.001), and no significant changes in single- received ,120 days of prescription of SO in combination pool Kt/V or normalized protein catabolic rate were observed with other PBs at FKC facilities (n5222) were compared (Table 3). Minor decreases in serum calcium concentrations with patients who completed 120 days. More specifically, (2%) and increases in intact PTH (9%) were observed during monthly mean sP during baseline (months 23, 22, and 21) follow-up (Table 3). The proportions of patients who received

Sucroferric oxyhydroxide therapy initiation Non-SO SO + Non-SO PB therapy (or) PB therapy PB naive

Month –3–2–1123456789101112

Quarter -Q1 Q1 Q2 Q3 Q4

Baseline Follow-Up Patient data were censored after FKC discharge, loss to follow-up, disenrollment from FreseniusRx, or end of SO prescription

Figure 2. | Study design including a three-month baseline and 12-month follow-up, analyzed quarterly (Q1 to Q4) and monthly. *Reasons for discharge from FKC includes transplantation, transfer to non-FKC facilities, withdrawal from dialysis, or death. 266 KIDNEY360

on this population (Table 4). Significant reductions in mean Table 1. Demographic characteristics of the study cohort sP and improvements in patients achieving an sP #5.5 mg/dl N5 ( 234) were observed independent of PB combinations. Patients 5 Measure Study Cohort who added SO to baseline calcium acetate therapy (N 54) achieved a greater than trifold increase in sP control (sP#5.5 Age, yr 51.8613.4 mg/dl; 13% at 2Q1 to 50% at Q4; P,0.001) and mean total PB 6 Dialysis vintage, mo 55.0 45.6 pill burden increased from 10.2 calcium acetate pills per day Female, n (%) 98 (42) – 1 Body mass index, kg/m2 33.168.9 at baseline to 11.2 13.7 (calcium acetate SO) pills per day Hemodialysis treatment time per week, h 10.761.6 at follow-up (P,0.001). There were no significant changes Race/ethnicity, n (%) observed in serum calcium (9.1 mg/dl at 2Q1 to 9.0 mg/dl White 123 (53) at Q4; P50.06) and intact PTH (502 pg/ml at 2Q1 to 569 pg/ Black 92 (39) ml at Q4; P50.24). Among the 94 patients who added SO to Other/unknown 19 (8) fi Hispanic/Latino 36 (15) baseline sevelamer therapy, there were signi cant improve- Comorbidities, n (%) ments in rates of achievement of sP #5.5 mg/dl (18% at Diabetes mellitus 138 (59) baseline to up to 45% at follow-up; P,0.001) and significant Congestive heart failure 69 (30) reductioninmeansP(Δ520.5 mg/dl; P,0.001). With the Charlson Comorbidity Index 4.762.0 Baseline phosphate binder, n (%)a addition of SO to existing sevelamer therapy, mean total Sevelamerb 96 (41) PB pill burden increased from 11.5 pills per day at 2Q1 to Calcium acetate 59 (25) 15.7 pills per day at Q1, but was significantly titrated Lanthanum carbonate 7 (3) c down over time (12.8 pills per day at Q4). There were PB polytherapy 56 (24) statistically significant decreases in mean serum calcium No PB recorded 16 (7) 2 , Clinical laboratory measures at baseline (9.2 mg/dl at Q1 to 9.0 mg/dl at Q4; P 0.001) and Serum phosphorus, mg/dl 6.761.4 increases in mean intact PTH (587 pg/ml at 2Q1 to 631 Serum calcium, mg/dl 9.160.6 pg/ml at Q4; P,0.001). Similarly, patients on other PB Intact PTH, pg/ml 5726493 6 combinations who added SO to their baseline PB treat- Serum albumin, g/dl 4.0 0.3 5 fi Single-pool Kt/V 1.760.1 ment regimens ( N 48) had signi cant reductions in mean sP and serum calcium and increasesinpatientsachieving # Data are presented as mean6SD, or n (%). PB, phosphate sP 5.5 mg/dl, mean total PB pill burden, and intact PTH binder; PTH, parathyroid hormone; CaAc, calcium acetate; Sev, levels. sevelamer carbonate; LC, lanthanum carbonate. aLast phosphate binder recorded at baseline. bIncludes 93 (97%) patients on sevelamer carbonate and three Subgroup Analysis of Completers (N5134) and (3%) patients on sevelamer hydrochloride. Noncompleters (N5100) cBaseline PB polytherapy included CaAc1Sev (17%), CaAc1LC A sensitivity analysis of patients who completed SO 1 (3%), and Sev LC (4%). therapy through Q4 (completers) and patients who discontinued SO before Q4 (noncompleters) was conducted to address the potential for bias from loss to follow-up. sP decreased sig- oral vitamin D and cinacalcet therapies increased over follow- nificantly from baseline (6.8 mg/dl in completers, 6.6 mg/dl up, whereas there was a slight decrease in the use of intra- in noncompleters) to follow-up (6.2–6.3 mg/dl in both venous vitamin D (Supplemental Table 1). groups; P,0.001), a mean decrease of 20.46 mg/dl and 20.38 mg/dl, respectively (Table 5). Proportions of individuals Subgroup Analysis of Patients Who Added SO Therapy to achieving an sP of #5.5 mg/dl improved significantly in both Baseline PB Therapy (N5196) completers (1135%) and noncompleters (176%). Among com- At baseline, SO was added to the existing PB for 84% pleters, although total PB pill burden increased from baseline (N5196) of the cohort; subgroup analyses were performed to Q1 with the addition of SO, non-SO PB pill burden was

Table 2. Follow-up phosphate binder therapy combinations with sucroferric oxyhydroxide by baseline phosphate binder (N5234)

PB Therapy Combinations at Follow-Up Baseline PBa CaAc1SO LC1SO Sev1SO CaAc1Sev1SO CaAc1LC1SO Sev1LC1SO CaAc1Sev1LC1SO

No PB recorded 4 (2) 1 (0.4) 11 (5) 0 0 0 0 CaAc 54 (23) 0 0 5 (2) 0 0 0 LC 0 5 (2) 0 0 1 (0.4) 1 (0.4) 0 Sev 0 0 94 (40) 2 (0.9) 0 0 0 CaAc1Sev 5 (2) 0 3 (1) 30 (13) 0 0 2 (0.8)b CaAc1LC 0 0 0 0 7 (3) 0 0 Sev1LC 0 0 3 (1) 0 0 6 (3) 0

Data are presented as n (%). PB, phosphate binder; CaAc, calcium acetate; SO, sucroferric oxyhydroxide; LC, lanthanum carbonate; Sev, sevelamer carbonate. aAt baseline, if multiple PB therapies were recorded, the last combination before SO initiation was included in the table. bPatients received LC prescription for ,30 d. KIDNEY360 1: 263–272, April, 2020 Combination Phosphate Binder Therapy with Sucroferric Oxyhydroxide, Molony et al. 267

A Baseline Follow-Up B Baseline Follow-Up

50% 20

15.8 15.5 40% 40% 15 13.6 37% 12.3 12.3 35% 30% 33% Total PB pills/day 10 5.5 mg/dL

≤ 20% 19% sP 4.2 4.3 4.6 Mean PB pills/day 5 4.0 10% SO pills/day -Q1 +Q1 +Q2 +Q3 +Q4 -Q1 +Q1 +Q2 +Q3 +Q4 0% 0

C Baseline Follow-Up D Baseline Follow-Up

7.5 0.2 0.1 -Q1 +Q1 +Q2 +Q3 +Q4 7.0 0.0 -0.1 6.72 6.5 -0.2 -0.3 6.32 6.23 6.25 Mean sP (mg/dL) 6.0 6.17 -0.4

sP from baseline (mg/dL) -0.41 Δ -0.5 -0.48 -Q1 +Q1 +Q2 +Q3 +Q4 -0.49 5.5 -0.6 -0.55

Figure 3. | Plots comparing baseline to SO follow-up. Plots of changes showed (A) increase in proportion (%) of patients with sP,5 5.5 mg/dl, (B) initial increase and then decrease in mean daily phosphate binder pill burden, (C) decrease in mean sP levels, and (D) mean decrease in sP from baseline (n5234). sP serum phosphorus. down-titrated over time such that, by Q4, there was no sig- included in the study cohort experienced a decrease in mean nificant increase in number of pills from 2Q1 (P50.38). In sP from 6.36 mg/dl at month 11 to 6.13 mg/dl at month 14, contrast, there was a consistent increase in total PB pill burden a mean decrease of 20.51 mg/dl from baseline. from baseline among noncompleters during all postbaseline time points (Q1–Q4), including treatment quarters post-SO discontinuation. Discussion In this retrospective cohort study, patients on HD initiat- Comparison of Patients Included versus Excluded from ing SO in combination with another PB demonstrated sig- Overall Study Cohort nificant reductions in sP. Such reductions were observed A sensitivity analysis was conducted to assess the degree across a spectrum of SO-containing PB regimens and were of selection bias introduced by the requirement of 120 days maintained for the duration of SO therapy (up to 1 year). of prescription of SO in combination with other PBs (Fig- Although .90% of patients were already being treated with ure 1). A comparison of 222 patients on HD who received at least one PB and nearly one quarter were receiving ,120 days of prescription of SO in combination with other combination therapy at baseline, the cohort exhibited PBs at FKC facilities was made with patients who completed marked hyperphosphatemia (mean sP56.7 mg/dl) before the 120 days (n5234). More specifically, monthly mean sP SO was prescribed (i.e., at baseline). After 1 year of PB during baseline (months 23, 22, and 21) and the first therapy including SO, 37% of patients attained an sP of 120 days of follow-up (months 11, 12, 13, and 14) were #5.5 mg/dl. Because SO therapy was often prescribed as evaluated. Before the initiation of SO therapy, mean sP was add-on therapy to other PBs, it is not surprising that patients 6.8 mg/dl, which was similar to the mean sP observed experienced an initial increase in pill burden. Continuation among patients in the study cohort (mean sP56.79 mg/dl; of SO therapy allowed for a decrease in total PB pill burden Supplemental Table 2). Post-baseline sP levels decreased over time, suggesting that clinicians down-titrated the dose from 6.39 mg/dl at month 11 to 6.30 mg/dl at month 14, a of other PBs (or discontinued other PBs) while up-titrating mean decrease of 20.45 mg/dl from baseline. Patients the dose of SO (Table 3). 6 KIDNEY360 268

Table 3. Longitudinal changes in clinical and laboratory parameters from baseline to follow-up (N5234)

Mean PB Pill Burden (pills/d) Serum Phosphorus (mg/dl) Mean Treatment Period sP #5.5 Serum Calcium Intact PTH Serum Albumin nPCR (g/kg Single-Pool All PB SO Non-SO PBa Mean mg/dlb (mg/dl) (pg/ml) (g/dl) per d) Kt/V

Baseline 2Q1 (referent) (N5234) 12.3 N/A (by design)c 12.3 6.72 45/234 (19) 9.15 584 4.0 1.06 1.71 Follow-up Q1 (N5234) 15.8d 4.0 11.8d 6.32d 78/234 (33)d 9.10e 568 3.97e 1.05 1.73 Q2 (N5234) 15.5d 4.2 11.3d 6.17d 93/233 (40)d 9.09e 565 3.97d 1.06 1.72 Q3 (N5202) 13.6d 4.3 10.6d,f 6.23d 64/185 (35)d 9.02d 629e 3.98e 1.04 1.70 Q4 (N5134) 12.3 4.6 10.0f 6.25d 46/125 (37)d 8.99d 634e 3.96e 1.01 1.68 P valueg ,0.001 N/A ,0.001 ,0.001 ,0.001 ,0.001 0.006 0.001 0.05 0.5

Data are presented as least-squared means or n/N (%). PB, phosphate binder; SO, sucroferric oxyhydroxide; sP, serum phosphorus; PTH, parathyroid hormone; nPCR, normalized protein catabolic rate; Q, quarter; N/A, not applicable; FreseniusRx, Fresenius specialty pharmacy; HD, hemodialysis; FKC, Fresenius Kidney Care. aNon-SO PB therapies included calcium acetate, lanthanum carbonate, and sevelamer. bPatients with missing sP were not included in the denominator N. cStatistical comparisons were not carried out because patients initiated SO therapy only at follow-up. dP,0.001. eP,0.05. fMean non-SO PB pill burden during treatment with PB combination therapy with SO. Data were censored when SO prescription ended, patients disenrolled from FreseniusRx, or when patients stopped receiving HD treatment at FKC. gP values compare summary measures with 2Q1 as the referent. KIDNEY360 1: 263–272, April, 2020 Combination Phosphate Binder Therapy with Sucroferric Oxyhydroxide, Molony et al. 269

Table 4. Serum phosphorus and phosphate binder pill burden among a subgroup of patients who added sucroferric oxyhydroxide to their baseline phosphate binder regimen (N5196)

Baseline Follow-Up Patients Who Added SO to their Baseline n P Valuea PB 2Q1 (referent) Q1 Q2 Q3 Q4

Serum phosphorus (mg/dl) All patients 196 6.73 6.31b 6.17b 6.22b 6.25b ,0.001 (Sev) to (Sev1SO) 94 6.80 6.33b 6.08b 6.26b 6.26b ,0.001 (CaAc) to (CaAc1SO) 54 6.55 6.26c 6.05b 6.03b 6.24 0.002 Otherd 48 6.80 6.33b 6.46c 6.32b 6.27b ,0.001 sP £5.5 mg/dl (%) All patients 196 18 34b 40b 37b 37b ,0.001 (Sev) to (Sev1SO) 94 18 35b 45b 35c 33 0.007 (CaAc) to (CaAc1SO) 54 13 32c 43b 44b 50c 0.004 Otherd 48 25 33 27 34 34 0.92 Total PB pill burden (pills/d) All patients 196 12.1 15.9b 15.8b 13.9b 12.7c ,0.001 (Sev) to (Sev1SO) 94 11.5 15.7b 16.0b 14.1b 12.8b ,0.001 (CaAc) to (CaAc1SO) 54 10.2 13.7b 13.8b 12.1b 11.2 ,0.001 Otherd 48 15.3 18.8b 17.5b 15.7 14.3c ,0.001 SO pill burden (pills/d)e All patients 196 N/A (by design) 4.0 4.2 4.3 4.6 N/A (Sev) to (Sev1SO) 94 4.0 4.3 4.5 4.7 (CaAc) to (CaAc1SO) 54 3.8 3.9 4.0 4.3 Otherb 48 4.2 4.4 4.4 4.6

Data are presented as least-squared means or percentages. SO, sucroferric oxyhydroxide; PB, phosphate binder; Q, quarter; Sev, sevelamer; CaAc, calcium acetate; sP, serum phosphorus; LC, lanthanum carbonate. aP values compare summary measures with 2Q1 as the referent. bP,0.001. cP,0.05. dOther PB combinations include patients who switched from LC to (LC1SO), (Sev1CaAc) to (Sev1CaAc1SO), (LC1CaAc) to (LC1CaAc1SO), and (Sev1LC) to (Sev1LC1SO). eStatistical comparisons were not carried out because patients initiated SO therapy only at follow-up.

Whereas combination therapy with PBs has been previ- sufficient phosphate binding capacity to maintain balance ously reported, we could identify only one other study among patients with typical dietary phosphorus intake (i.e., specifically designed to examine SO as a component of 1500 mg/d). Prescriptions that combined two PBs were PB combination therapy (33). In that 12-week exploratory calculated to have significantly increased phosphate bind- study, 35 adult patients on HD with sP between 3.5 and ing capacity than prescriptions for a single PB (451 versus 6.0 mg/dl maintained on calcium carbonate plus sevelamer 236 mg/d, P,0.001). Potential benefits of combination PB hydrochloride were switched to calcium carbonate plus SO. therapy are also supported by findings from COSMOS SO was administered three times daily at total daily doses of (18,34). Such findings have led some experts to suggest that 750–3000 mg and calcium carbonate doses were to be held combination PB therapy be considered to control sP in pa- constant. Investigators found that, while simultaneously tients when monotherapy is inadequate (i.e., before switching reducing pill burden, sP concentrations were maintained agents) (34). between 3.5 and 6.0 mg/dl in most (91%) patients, with the Nonadherence to prescribed PB regimens is common, lowest dose of SO when prescribed concomitantly with with one study finding that only 43% of United States calcium carbonate. This analysis examined combination patients reported complete adherence in the prior month therapy with SO among a larger cohort of patients who (36,37). Because pill burden has been associated with were difficult to treat and over a longer follow-up length. reduced adherence and reduced sP control, it is a relevant Additionally, our study population demonstrated more consideration in the management of hyperphosphatemia severe hyperphosphatemia at baseline; fewer than one fifth (23,37,38). In this study, combination PB therapy with SO, of patients exhibited an sP of #5.5 mg/dl at baseline. most often as an addition of SO to an existing PB regimen, There is biologic plausibility supporting combination PB resulted in an initial increase in pill burden. With continued therapy use to treat hyperphosphatemia in patients on HD. SO use, however, PB pill burden was gradually reduced Specifically, PBs may have variable phosphate binding while significantly reduced sP levels were maintained. capacities throughout the gastrointestinal tract (34). In 2012, This observational study presents data from the largest Huml et al. (35) examined the phosphorus binding capacity cohort of patients on HD prescribed combination PB ther- of PB prescriptions in a national sample of patients on HD. A apy with SO reported to date. Beyond the observational majority (59%) of PB prescriptions were determined to have nature of the study, the results should be considered in light insufficient binding capacity to maintain phosphorus bal- of several limitations. We did not consider the dose of ance if patients restricted their dietary phosphate intake to prescribed PBs or the frequency of administration in this 1000 mg per day. None of the PB prescriptions assessed had analysis. It is possible that different PBs were being 270 KIDNEY360

prescribed for administration at different times of the day (e.g., with meals versus with snacks) or being dosed variably throughout the day. The use of variable PB dosing informed c

c by phosphate intake may help to compensate for variable 0 4.3 4.4 4.4 dietary phosphate intake (39). Our study also used a single source of prescription data, so the possibility that medications were obtained through other pharmacy services or over the counter, as in the case of calcium carbonate, cannot be excluded. Prescription data, although informative, is not a surrogate for actual patient adherence with prescribed regimens. The reasons for discontinuation of SO therapy

3.8 4.1 4.2 4.4 were not captured in our electronic health records database,

ts who discontinued SO before Q4. sP, but reasons may include lack of effectiveness, nontolerabil- ity, nonadherence to PB therapy regimen, insurance cover- age, and out-of-pocket costs. Data on safety (e.g., adverse reactions) were not available in the clinical database. Lastly, we cannot draw any conclusions regarding SO treatment ﬁ a a b b and effects on mortality, signi cant morbidities, or quality

0.001 N/Aof life. N/A Future studies should examine the effect on clinical 15.5 15.3 14.7 14.9 , outcomes such as hospital admissions or mortality and patient-centered outcomes such as quality of life. We did not have access to data regarding the clinical rationale for PB initiation/discontinuation or dose adjust-

100) ments which allows for the possibility of a selection bias. A b b b 5 conducted sensitivity analysis assessed selection bias due to N 0.001 12.5 16.0 16.0 13.7

, early stopping of SO therapy before 120 days and found that, during SO treatment, included and excluded patients had similar decreases in sP. To assess potential differences between this study population and patients prescribed SO monotherapy, we examined a previously reported, real- world cohort of patients on HD prescribed SO monotherapy b b b b

36 38 36 34 (Supplemental Table 3) (31). Relative to this study, patients switching from another PB to SO monotherapy had higher 134) and noncompleters (

5 baseline sP, lower daily PB pill burden, and fewer comor- N bidities. These ﬁndings suggest that combination therapy

5.5 mg/dl (%) Total PB Pills per Day SO Pills per Day with SO was initiated after baseline PB therapy had been up- # 0.001. titrated but that clinicians were still not satisﬁed with , P a a a b a attained sP levels. 41 36 37 31 0.001 0.04

, In this observational cohort study, SO was associated with signiﬁcant improvement in sP when initiated as part of combination therapy for hyperphosphatemia. The ﬁnd- ings support the use of SO in combination with other PBs to allow for a treatment regimen tailored to the needs of a a b b patients and clinicians. 0.001 6.33 6.39 6.16 6.32

, Acknowledgments Q1 as the referent.

– Medical writing and editing support was provided by Adam Perahia of NorthStar Strategic Consulting, LLC, via funding by Fresenius Medical Care Renal Therapies Group. sP (mg/dl) sP

a a a a Author Contributions All authors conceptualized thestudy,wereresponsiblefor 0.001 6.20 6.25 6.16

, investigation and methodology, and reviewed and edited the Completers Noncompleters Completers Noncompleters Completers Noncompleters Completersmanuscript; Noncompleters L. Ficociello was responsible for project administration; L. Ficociello and V. Parameswaran were responsible for data curation, formal analysis, validation, and visualization; L. Ficociello, R. Kossmann, and D. Molony were responsible for supervision; and L. Ficociello, R. Kossmann, and C. Mullon were responsible for resources. d c c 0.05. Q1 6.80 6.62Disclosures 17 22 12.8 11.6 N/A by design N/A by design values compare summary measures with , Q4 Q2 Q3 2 Q1 6.31 value Treatment Period P P Patients in the noncompleters group may have discontinued the use of SO. L. Ficociello, R. Kossmann, C. Mullon, and V. Parameswaran are Table 5. Serum phosphorus and phosphate binder pill burden among completers ( P b c d Baseline Data are presented as least-squaredserum means or phosphorus; percentages. PB, Completers were phosphate patients binder; who SO, received SO sucroferric treatment oxyhydroxide. through Q4; noncompleters were patien Follow-up employees of Fresenius Medical Care Renal Therapies Group. R. KIDNEY360 1: 263–272, April, 2020 Combination Phosphate Binder Therapy with Sucroferric Oxyhydroxide, Molony et al. 271

Kossmann and C. Mullon own stock in Fresenius Medical Care North A, Bos WJ, Covic A, Rodrı´guez-Garcıá M, Sańchez JE, Rodrı´guez- America. R. Kossmann is on the board of directors of Advanced Renal Puyol D, Cannata-Andia JB; COSMOS group: Improvement of mineral and bone metabolism markers is associated with better Technologies. D. Molony is professor of medicine at the McGovern survival in haemodialysis patients: The COSMOS study. Nephrol Medical School, University of TexasHouston,andreportspersonal Dial Transplant 30: 1542–1551, 2015 fees from Fresenius Medical Care outside the submitted work. 12. Taketani Y, Koiwa F, Yokoyama K: Management of phosphorus load in CKD patients. Clin Exp Nephrol 21[Suppl 1]: 27–36, Funding 2017 This work was supported by Fresenius Medical Care Renal 13. Sinha A, Prasad N: Dietary management of hyperphosphatemia in chronic kidney disease. Clinical Queries: Nephrology. 3: Therapies Group. 38–45, 2014 14. Daugirdas JT: Removal of phosphorus by hemodialysis. Semin Supplemental Material Dial 28: 620–623, 2015 This article contains the following supplemental material online 15. National Kidney Foundation: K/DOQI clinical practice guide- at http://kidney360.asnjournals.org/lookup/suppl/doi:10.34067/ lines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42[Suppl 3]: S1–S201, 2003 KID.0000332019/-/DCSupplemental. 16. Lopes AA, Tong L, Thumma J, Li Y, Fuller DS, Morgenstern H, Supplemental Table 1. Longitudinal changes in prescription pat- Bommer J, Kerr PG, Tentori F, Akiba T, Gillespie BW, Robinson terns of mineral bone disease medications (N5234). BM, Port FK, Pisoni RL: Phosphate binder use and mortality Supplemental Table 2. Comparison of serum phosphorus levels among hemodialysis patients in the Dialysis Outcomes and between patients in the study cohort (N5234) and patients who Practice Patterns Study (DOPPS): Evaluation of possible con- founding by nutritional status. Am J Kidney Dis 60: 90–101, 2012 stopped combination therapy with SO within 120 days of SO 17. Isakova T, Gutie´rrez OM, Chang Y, Shah A, Tamez H, Smith K, 5 initiation (N 222). Thadhani R, Wolf M: Phosphorus binders and survival on Supplemental Table 3. Comparison of demographic character- hemodialysis. J Am Soc Nephrol 20: 388–396, 2009 istics between study cohort and a historic cohort of hemodialysis 18. Cannata-Andıá JB, Fernańdez-Martıń JL, Locatelli F, London G, patients prescribed SO monotherapy. Gorriz JL, Floege J, Ketteler M, Ferreira A, Covic A, Rutkowski B, Memmos D, Bos WJ, Teplan V, Nagy J, Tielemans C, Verbeelen D, Goldsmith D, Kramar R, Martin PY, Wu¨thrich RP, Pavlovic D, Benedik M, Sańchez JE, Martıńez-Camblor P, Naves-Dıáz M, References Carrero JJ, Zoccali C: Use of phosphate-binding agents is asso- 1. Hruska KA, Mathew S, Lund R, Qiu P, Pratt R: Hyper- ciated with a lower risk of mortality. Kidney Int 84: 998–1008, phosphatemia of chronic kidney disease. Kidney Int 74: 148–157, 2013 2008 19. US-DOPPS (Dialysis Outcomes and Practice Patterns Study) 2. Vervloet MG, van Ballegooijen AJ: Prevention and treatment of Practice Monitor: Phosphate binder use, last 3 months. 2019. hyperphosphatemia in chronic kidney disease. Kidney Int 93: Available at: https://www.dopps.org/DPM/Files/maxPBINDER_ 1060–1072, 2018 use_c_overallTAB.htm. Accessed July 8, 2019 3. Martin KJ, Gonza´lez EA: Prevention and control of phosphate 20. US-DOPPS (Dialysis Outcomes and Practice Patterns Study) retention/hyperphosphatemia in CKD-MBD: What is normal, Practice Monitor: Serum phosphorous (most recent). 2019. when to start, and how to treat? Clin J Am Soc Nephrol 6: Available at: https://www.dopps.org/DPM/Files/phos- 440–446, 2011 phmgdl_c_overallTAB.htm. Accessed July 8, 2019 4. Tonelli M, Pannu N, Manns B: Oral phosphate binders in patients 21. Sekar A, Kaur T, Nally JV, Rincon-Choles H, Jolly S, Nakhoul GN: with kidney failure. N Engl J Med 362: 1312–1324, 2010 Phosphorus binders: The new and the old, and how to choose. 5. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Cleve Clin J Med 85: 629–638, 2018 Andress DL: Prevalence of abnormal serum vitamin D, PTH, 22. Wang S, Alfieri T, Ramakrishnan K, Braunhofer P, Newsome BA: calcium, and phosphorus in patients with chronic kidney disease: Serum phosphorus levels and pill burden are inversely associated Results of the study to evaluate early kidney disease. Kidney Int with adherence in patients on hemodialysis. Nephrol Dial 71: 31–38, 2007 Transplant 29: 2092–2099, 2014 6. Vervloet MG, Sezer S, Massy ZA, Johansson L, Cozzolino M, 23. Chiu YW, Teitelbaum I, Misra M, de Leon EM, Adzize T, Mehrotra Fouque D; ERA–EDTA Working Group on Chronic Kidney R: Pill burden, adherence, hyperphosphatemia, and quality of life Disease–Mineral and Bone Disorders and the European Renal in maintenance dialysis patients. Clin J Am Soc Nephrol 4: Nutrition Working Group: The role of phosphate in kidney dis- 1089–1096, 2009 ease. Nat Rev Nephrol 13: 27–38, 2017 24. Velphoro (sucroferric oxyhydroxide) [package insert]. Wal- 7. Covic A, Kothawala P, Bernal M, Robbins S, Chalian A, Gold- tham, MA; Fresenius Medical Care North America; revised April smith D: Systematic review of the evidence underlying the 2018. association between mineral metabolism disturbances and risk of 25. Koiwa F, Terao A: Dose-response efficacy and safety of PA21 in all-cause mortality, cardiovascular mortality and cardiovascular Japanese hemodialysis patients with hyperphosphatemia: A events in chronic kidney disease. Nephrol Dial Transplant 24: randomized, placebo-controlled, double-blind, Phase II study 1506–1523, 2009 [published correction appears in Clin Exp Nephrol 21: 523, 8. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, 2017]. Clin Exp Nephrol 21: 513–522, 2017 Strippoli GF: Serum levels of phosphorus, parathyroid hormone, 26. Koiwa F, Yokoyama K, Fukagawa M, Terao A, Akizawa T: Efficacy and calcium and risks of death and cardiovascular disease in and safety of sucroferric oxyhydroxide compared with sevelamer individuals with chronic kidney disease: A systematic review and hydrochloride in Japanese haemodialysis patients with hyper- meta-analysis. JAMA 305: 1119–1127, 2011 phosphataemia: a randomized, open-label, multicentre, 12-week 9. Wang M, Obi Y, Streja E, Rhee CM, Lau WL, Chen J, Hao C, phase III study. Nephrology (Carlton) 22: 293–300, 2017 Hamano T, Kovesdy CP, Kalantar-Zadeh K: Association of 27. Sprague SM, Ketteler M, Covic AC, Floege J, Rakov V, Walpen S, parameters of mineral bone disorder with mortality in patients on Rastogi A: Long-term efficacy and safety of sucroferric oxy- hemodialysis according to level of residual kidney function. Clin hydroxide in African American dialysis patients. Hemodial Int 22: J Am Soc Nephrol 12: 1118–1127, 2017 480–491, 2018 10. Rivara MB, Ravel V, Kalantar-Zadeh K, Streja E, Lau WL, Nis- 28. Floege J, Covic AC, Ketteler M, Mann J, Rastogi A, Spinowitz B, senson AR, Kestenbaum B, de Boer IH, Himmelfarb J, Mehrotra R: Rakov V, Lisk LJ, Sprague SM: One-year efficacy and safety of the Uncorrected and albumin-corrected calcium, phosphorus, and iron-based phosphate binder sucroferric oxyhydroxide in patients mortality in patients undergoing maintenance dialysis. J Am Soc on peritoneal dialysis. Nephrol Dial Transplant 32: 1918–1926, Nephrol 26: 1671–1681, 2015 2017 11. Fernańdez-Martıń JL, Martıńez-Camblor P, Dionisi MP, Floege J, 29. Floege J, Covic AC, Ketteler M, Rastogi A, Chong EM, Gaillard S, Ketteler M, London G, Locatelli F, Gorriz JL, Rutkowski B, Ferreira Lisk LJ, Sprague SM; PA21 Study Group: A phase III study of the 272 KIDNEY360

efficacy and safety of a novel iron-based phosphate binder in 35. Huml AM, Sullivan CM, Leon JB, Sehgal AR: The adequacy of dialysis patients. Kidney Int 86: 638–647, 2014 phosphorus binder prescriptions among American hemodialysis 30. Kendrick J, Parameswaran V, Ficociello LH, Ofsthun NJ, Davis S, patients. Ren Fail 34: 1258–1263, 2012 Mullon C, Kossmann RJ, Kalantar-Zadeh K: One-year historical 36. Umeukeje EM, Mixon AS, Cavanaugh KL: Phosphate-control cohort study of the phosphate binder sucroferric oxyhydroxide in adherence in hemodialysis patients: Current perspectives. Patient patients on maintenance hemodialysis. J Ren Nutr 29: 428–437, Prefer Adherence 12: 1175–1191, 2018 2019 37. Fissell RB, Karaboyas A, Bieber BA, Sen A, Li Y, Lopes AA, Akiba 31. Coyne DW, Ficociello LH, Parameswaran V, Anderson L, Vemula T, Bommer J, Ethier J, Jadoul M, Pisoni RL, Robinson BM, Tentori S, Ofsthun NJ, Mullon C, Maddux FW, Kossmann RJ, Sprague SM: F: Phosphate binder pill burden, patient-reported non-adherence, Real-world effectiveness of sucroferric oxyhydroxide in patients and mineral bone disorder markers: Findings from the DOPPS. on chronic hemodialysis: A retrospective analysis of pharmacy Hemodial Int 20: 38–49, 2016 data. Clin Nephrol 88: 59–67, 2017 38. Covic A, Rastogi A: Hyperphosphatemia in patients with ESRD: 32. Gray K, Ficociello LH, Hunt AE, Mullon C, Brunelli SM: Phos- Assessing the current evidence linking outcomes with treatment phate binder pill burden, adherence, and serum phosphorus adherence. BMC Nephrol 14: 153, 2013 control among hemodialysis patients converting to sucroferric 39. Leung S, McCormick B, Wagner J, Biyani M, Lavoie S, Imtiaz R, oxyhydroxide. Int J Nephrol Renovasc Dis 12: 1–8, 2019 Zimmerman D: Meal phosphate variability does not support fixed 33. Koiwa F, Yokoyama K, Fukagawa M, Akizawa T: Efficacy and dose phosphate binder schedules for patients treated with peri- safety of sucroferric oxyhydroxide and calcium carbonate in toneal dialysis: A prospective cohort study. BMC Nephrol 16: hemodialysis patients. Kidney Int Rep 3: 185–192, 2017 205, 2015 34. Vervloet MG: Hyperphosphataemia: Which phosphate binder? Nephrol Dial Transplant 33: 1091–1093, 2018 Received: October 17, 2019 Accepted: March 5, 2020 Supplementary Table of Contents Supplementary Table 1. Longitudinal Changes in Prescription Patterns of Mineral Bone Disease Medications (N=234)

Supplementary Table 2. Comparison of Serum Phosphorus Levels between Patients in the Study Cohort (N=234) and Patients who Stopped Combination Therapy with SO within 120 Days of SO Initiation (N=222)

Supplementary Table 3. Comparison of Demographic Characteristics between Study Cohort and a Historic Cohort of Hemodialysis Patients Prescribed SO Monotherapy

Supplementary Table 1. Longitudinal Changes in Prescription Patterns of Mineral Bone Disease Medications (N=234)

Intravenous Vitamin D Oral Vitamin D Cinacalcet

Doxercalciferol Calcitriol dose, Cinacalcet dose, Use, % Use, % Use, % dose, µg/week mcg/day mg/day

-Q1 50.0 43.3 45.7 2.1 50.0 49.4 (referent) Baseline

Q1 49.6 41.7 52.6 * 1.5 54.7 * 51.3 * up - Q2 49.3 42.0 53.8 * 1.4 53.4 * 51.1 * Q3 47.8 * 34.5 † 54.5 † 0.9 * 59.0 * 53.1 †

Follow Q4 43.7 † 36.6 * 57.5 † 0.7 * 68.0 † 52.4 †

P-Value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Note: Data are presented as least-squared means or % P-values compare quarterly summary measures with –Q1 as the referent. *P<0.05; †P<0.001

Supplementary Table 2. Comparison of Serum Phosphorus Levels between Patients in the Study Cohort (N=234) and Patients who Stopped Combination Therapy with SO within 120 Days of SO Initiation (N=222)

Baseline mean sP Follow-up mean sP Groups n Month Month Month -1 Month Month Month Month P-Value -3 -2 (referent) 1 2 3 4 Study cohort: Patients who completed ≥ 120 days of combination therapy with SO (N=234)

All patients in the study 234 6.61 6.81 6.79 6.36 † 6.35 † 6.29 † 6.13 † <0.001 Excluded; patients who completed < 120 days of combination therapy with SO (N=222)

Patients who were excluded 222 6.50 * 6.66 6.80 6.39 † 6.37 † 6.38 † 6.30 † <0.001

Discharged from FKC or 49 6.27 * 6.60 6.50 6.20 * 6.03 * 6.47 6.07 * 0.006 disenrolled from FreseniusRx a

Switched from (SO + non-SO PB) to SO 26 6.35 6.44 6.60 6.0 6.64 6.05 6.26 0.14 monotherapy Switched from (SO + non-SO PB) to 95 6.56 * 6.62 6.92 6.56 * 6.56 * 6.47 * 6.46 * <0.001 non-SO PB monotherapy Switched from (SO + non-SO PB) to 52 6.66 6.90 7.0 6.39 * 6.66 6.48 * 6.61 0.011 non-SO PB polytherapy

Note: Data are presented as least-squared means P-values compare summary measures with month -1 as the referent. *P<0.05; †P<0.001 a Some patients were discharged from FKC (transplantation, transfer to non-FKC facilities, withdrawal from dialysis, or death), and did not have follow-up pharmacy or lab records. Results for patients who disenrolled from FreseniusRx, but continued to receive HD care at FKC are presented. Abbreviations: FKC, Fresenius Kidney Care; FreseniusRx, Fresenius specialty pharmacy; HD, hemodialysis; PB, phosphate binder; ref, reference; sP, serum phosphorus; SO, sucroferric oxyhydroxide

Supplementary Table 3. Comparison of Demographic Characteristics between Study Cohort and a Historic Cohort of Hemodialysis Patients Prescribed SO Monotherapy

Measure Study Cohort Comparative Cohort* Number of patients 234 1029 Age, years 51.8 ± 13.4 52.4 ± 13.0 Dialysis vintage, months 55.0 ± 45.6 53.3 ± 46.7 Female, n (%) 98 (41.9) 474 (46.1) Body mass index, kg/m2 33.1 ± 8.9 32.3 ± 8.8 Race/ethnicity, n (%) White 123 (52.6) 522 (50.7) Black 92 (39.3) 452 (43.9) Other / unknown 19 (8.1) 55 (5.4) Hispanic/Latino 36 (15.4) 163 (15.8) Comorbidities, n (%) Diabetes mellitus 138 (59.0) 605 (58.8) Congestive heart failure 69 (29.5) 215 (20.9) Charlson Co-Morbidity Index 4.7 ± 2.0 3.8 ± 1.6 a Baseline phosphate binder b, n (%) Sevelamer 96 (41) 629 (61.1) Calcium acetate 59 (25.2) 242 (23.5) Lanthanum carbonate 7 (3) 72 (7.0) PB polytherapy c 56 (23.9) - No PB recorded 16 (6.8) - Recorded switch between PB d - 86 (8.4) PB pill burden, pills/d 12.3 ± 6.4 9.6 ± 4.3 Clinical lab measures at baseline Serum phosphorus, mg/dL 6.70 ± 1.43 6.93 ± 1.39 Serum calcium, mg/dL 9.14 ± 0.63 9.24 ± 0.69 Intact PTH, pg/mL 572 ± 493 578 ± 480 Serum albumin, g/dL 4.0 ± 0.3 4.0 ± 0.3

Note: Data are presented as mean ± standard deviation, or n(%) * Comparative reference population included a cohort of 1029 HD patients who were prescribed SO monotherapy as part of routine clinical care at FKC clinics and previously published 28 a Charlson comorbidity index was not included in reference 28 b Last recorded phosphate binder was presented for the study cohort c Baseline phosphate binder polytherapy in the study cohort included CaAc + Sev (17%), CaAc + LC (3%), and Sev + LC (3.9%) d Recorded switch between phosphate binder therapies in the comparative cohort included patients who switched between Sev and CaAc (5.7%), CaAc and LC (1%), and Sev and LC (1.7%) Abbreviations: CaAc, calcium acetate; HD, hemodialysis; LC, lanthanum carbonate; PB, phosphate binder; PTH, intact parathyroid hormone; Sev, sevelamer carbonate