A 6-Month clinical practice pilot study of sucroferric oxyhydroxide on nutritional status in patients on peritoneal dialysis

Participants were enrolled between January 2020 and February 2021 at the University of Colorado Anschutz Medical Campus. The study eligibility criteria included participants with age ≥ 18 years, on peritoneal (automated) dialysis at least 3 months; treatment Kt/V of ≥ 1.7; serum phosphate ≥ 5.5 mg/dL or ≤ 5.5 mg/dL on a binder other than SO; serum albumin ≤ 3.8 g/dL; able to provide consent; and ability to complete self-reported questionnaires. Participants were excluded for inadequate dialysis treatment, current use of SO; significant comorbid conditions with life expectancy less than 6 months; active malignancy; recent episodes of peritonitis; pregnancy or planning to become pregnant; anticipated kidney transplantation within 6 months; or known adverse side effects to SO. All participants provided written informed consent before study entry. The study protocol and informed written consent were approved by the Colorado Multiple Institutional Review Board (Aurora, CO) and was first registered at ClinicalTrials.gov (NCT04046263) on 06/08/2019. All procedures performed were in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from the subjects as specified in the ICMJE Recommendations.

The study was a 6-month prospective, open-label, pilot study. Participants who met eligibility criteria and provided informed consent underwent screening and began a 2-week washout period if previously on a phosphate binder. Following baseline testing, participants were started on SO and underwent follow-up testing at months 3 and 6 and monthly checks for routine laboratory values, adverse events, and compliance. No additional dietary counseling, other than standard of care practice, was provided to participants during the study. Laboratory and clinical treatment data were obtained from participants treatment records throughout the course of the study. Clinical blood laboratory values were collected from standard of care blood draws every 3 months. The PD treatment schedules and parameters were consistent over the course of the study.

Participants were started on 1 tablet (500 mg) SO 3 times daily with meals. The SO dosage was titrated monthly in increments of 500 mg (1 tablet) per day until serum phosphate was < 5.5 mg/dL.

The primary study endpoints were change in serum phosphorus and serum albumin, and phosphorus-attuned albumin. Secondary endpoints included changes in appetite. Phosphorus-attuned albumin was defined and calculated by dividing serum albumin by serum phosphorus levels (i.e. adjustment, units of 10x³) [9]. Adjustment of albumin with serum phosphorus aims to evaluate if lower protein intake contributed to lower serum phosphorus and/or albumin levels, which is a potential concern for malnutrition and mortality [9‐11]. In this regard, ideally patients reduce serum phosphorus levels while maintaining or increasing albumin represented by increased in phosphorus-attuned albumin [9‐11]. Phosphate binder pill burden and pill compliance were calculated based off phosphate binder prescription upon enrollment, during the study, and actual reported or accounted for pill consumption. Participants completed the Appetite and Diet Assessment Tool (ADAT) and 3-day dietary records at each of the three major study time-points [12]. Research staff provided instructions for patients to record dietary history and dietary records were entered into the National Institutes of Health Automated Self-Administered 24-h assessment tool (ASA-24) for nutrient analysis. Participants also completed a gastrointestinal symptom and side effects questionnaire each month.

Descriptive statistics were used to summarize all data. For example, mean ± SD or median and interquartile range (IQR) were calculated for a continuous variable if appropriate, and frequency and proportion were reported for a categorical or ordinal variable. Data transformation was performed before further analysis if appropriate. The primary analyses consisted of repeated measures data analysis with mixed effects model for a continuous outcome and with generalized estimating equations for a categorical or ordinal outcome. All participants with at least one measure on an outcome variable were included in analysis. The paired t-test was used in the pre-post comparison of pill count. The two-sided significance level of 0.05 was used in making a conclusion. All analyses were performed using SAS software, version 9.4 (SAS Institute Inc.).

Seventeen patients were enrolled in the study and 12 patients completed the entire study. One patient completed the study early due to receiving a kidney transplant. Baseline characteristics are shown in Table 1. Participants had a mean age of 55 ± 14 years. The mean dialysis vintage was 3.6 ± 2.5 years. The majority of patients were male (65%) and White/Caucasian (82%). Six individuals (35%) identified as Hispanic/Latino. Eighty-eight percent of patients were on a phosphate binder at baseline and the majority were on sevelamer or a combination of sevelamer and calcium-based binders (Table 1). Median baseline phosphate binder burden prior to washout was 12.0 (9.0 – 15.0) pills/day. Average compliance for SO over the course of the study was 73.9 ± 24.5%.

Participants had a significant reduction in serum phosphorus at both 3 months and 6 months, when compared to baseline (all p < 0.01, Table 2). Approximately 55% of patients achieved a serum phosphorus level of < 5.5 mg/dL at month 6. However, there were no significant changes in serum albumin at any time-point (p > 0.05). There was a significant increase in phosphorus-attuned albumin, driven by an increase from baseline to month 3 that was maintained at month 6 (all p < 0.05). Changes in serum phosphorus, albumin, and phosphorus-attuned albumin are depicted in Fig. 1. There were no significant changes in parathyroid hormone (PTH) levels with SO use (p > 0.05). Phosphate pill burden significantly decreased from a median of 12 (10.5 – 13.0) pills/day before SO to 5.0 (3.0 – 6.0) pills/day with SO (p < 0.01) for subjects who completed the study.

There did not appear to be any changes in appetite or desire to change diet with SO (p > 0.05, Table 3). There were also no significant changes in self-reported appetite within the ADAT (all p > 0.05), except for an increase in desire to change diet at month 3 (p = 0.037), which was no longer present at month 6, when compared to baseline (p > 0.05, Table 3).

At baseline, 41% of participants self-reported difficulty following their diet. The five major reasons for difficulty following their diet included: “Do not feel like the foods I am supposed to eat” (12%), “Do not feel like cooking” (10%), “Do not feel like preparing food” (6%), “Do not understand what I am supposed to eat” (4%), and “Do not have control over my food choices” (4%). The majority of open-ended responses for participants wanting to change diet generally fell into the category of desire to liberalize their diet for more freedom in food choices. Notably, 83% of participants reported going out to eat throughout the course of the study, with a mean frequency of 3.7 ± 2.9 times per month. Methods of eating out included 57% fast food, 41% restaurant, 14% friend/relatives, and 8% cafeteria. At home, greater than 90% of participants reported having a stove, refrigerator, freezer, microwave oven, and food processor/blender (60% reported having a toaster oven).

There were no serious adverse events over the course of the study related to the study drug. Twelve patients (71%) completed the study. Two patients withdrew due to side effects (diarrhea), 1 patient changed to hemodialysis and 2 patients died (unrelated to the study). One patient had peritonitis following a hospitalization for COVID-19 infection. Participants did not require reduction of study medications during the study, except for one subject that subsequently withdrew from participation. At baseline, 94% (n = 17) of participants had reported experiencing existing gastrointestinal symptoms. This decreased to 82% (n = 9) of participants by month 6 of the study (Table 4). For those who reported gastrointestinal symptoms, the overall reported frequency count (present vs. not present) of each over the whole course of the study was 49% (n = 34) for diarrhea, 44% for constipation (n = 31), 28% for bloating (n = 19), 26% (n = 18) for nausea, 25% (n = 17) for vomiting (Table 4). Notably, there were seven self-reported cases of “severe” gastrointestinal symptoms reported (n = 2 diarrhea, n = 3 constipation, and n = 2 bloating), including two that were already present at baseline (n = 1 constipation and n = 1 bloating). Subjects attributed these symptom events to their non-study drug medications approximately 19% (n = 13) of the time. Significantly fewer patients reported bloating with SO. For other self-reported side effects over the 6-month course of the study, participants reported 84% (n = 56) black/tarry/or bloody stools, 25% (n = 17) color changes in stools, and 4% (n = 3) rashes. However, these self-reported symptoms numerically decreased in frequency over the course of the study.