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Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.
Mathur, VS, Wesson, DE, Tangri, N, Li, E, Bushinsky, DA
BMC nephrology. 2022;(1):82
Abstract
BACKGROUND Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. METHODS This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial. RESULTS At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002). CONCLUSIONS Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.
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Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.
Weir, MR, Bakris, GL, Gross, C, Mayo, MR, Garza, D, Stasiv, Y, Yuan, J, Berman, L, Williams, GH
Kidney international. 2016;(3):696-704
Abstract
Elevated serum aldosterone can be vasculotoxic and facilitate cardiorenal damage. Renin-angiotensin system inhibitors reduce serum aldosterone levels and/or block its effects but can cause hyperkalemia. Patiromer, a nonabsorbed potassium binder, decreases serum potassium in patients with chronic kidney disease on renin-angiotensin system inhibitors. Here we examined the effect of patiromer treatment on serum aldosterone, blood pressure, and albuminuria in patients with chronic kidney disease on renin-angiotensin system inhibitors with hyperkalemia (serum potassium 5.1-6.5 mEq/l). We analyzed data from the phase 3 OPAL-HK study (4-week initial treatment phase of 243 patients; 8-week randomized withdrawal phase of 107 patients). In the treatment phase, the (mean ± standard error) serum potassium was decreased concordantly with the serum aldosterone (-1.99 ± 0.51 ng/dl), systolic/diastolic blood pressure (-5.64 ± 1.04 mm Hg/-3.84 ± 0.69 mm Hg), and albumin-to-creatinine ratio (-203.7 ± 54.7 mg/g), all in a statistically significant manner. The change in the plasma renin activity (-0.44 ± 0.63 μg/l/hr) was not significant. In the withdrawal phase, mean aldosterone levels were sustained with patiromer (+0.23 ± 1.07 ng/dl) and significantly increased with placebo (+2.78 ± 1.25 ng/dl). Patients on patiromer had significant reductions in mean systolic/diastolic blood pressure (-6.70 ± 1.59/-2.15 ± 1.06 mm Hg), whereas those on placebo did not (-1.21 ± 1.89 mm Hg/+1.72 ± 1.26 mm Hg). Significant changes in plasma renin activity were found only in the placebo group (-3.90 ± 1.41 μg/l/hr). Thus, patiromer reduced serum potassium and aldosterone levels independent of plasma renin activity in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.
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A Phase 1 dose-ranging study examining the effects of a superabsorbent polymer (CLP) on fluid, sodium and potassium excretion in healthy subjects.
Henderson, LW, Dittrich, HC, Strickland, A, Blok, TM, Newman, R, Oliphant, T, Albrecht, D
BMC pharmacology & toxicology. 2014;:2
Abstract
BACKGROUND CLP is an orally administered, non-absorbed, superabsorbent polymer being developed to increase fecal excretion of sodium, potassium and water in patients with heart failure and end-stage renal disease. This study was conducted to evaluate the safety of CLP, and to explore dose-related effects on fecal weight, fecal and urine sodium and potassium excretion, and serum electrolyte concentrations. METHODS This Phase 1, open-label, dose-escalation study included 25 healthy volunteers, who were administered CLP orally immediately prior to four daily meals for 9 days at doses of 7.5, 15.0, and 25.0 g/day (n = 5/group). An additional dose group received 15.0 g/day CLP under fasting conditions, and an untreated cohort (n = 5) served as control. Twenty-four-hour fecal and urinary output was collected daily. Samples were weighed, and sodium, potassium, and other ion content in stool and urine were measured for each treatment group. Effects on serum cation concentrations, other standard laboratory values, and adverse events were also determined. RESULTS At doses below 25.0 g/day, CLP was well tolerated, with a low frequency of self-limiting gastrointestinal adverse events. CLP increased fecal weight and fecal sodium and potassium content in a dose-related manner. Concomitant dose-related decreases in urinary sodium and potassium were observed. All serum ion concentrations remained within normal limits. CONCLUSIONS In this study, oral CLP removed water, sodium and potassium from the body via the gastrointestinal tract in a dose related fashion. CLP could become useful for patients with fluid overload and compromised kidney function in conditions such as congestive heart failure, salt sensitive hypertension, chronic kidney disease and end stage renal disease. TRIAL REGISTRATION NCT01944007.
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A new formulation of tolevamer, a novel nonantibiotic polymer, is safe and well-tolerated in healthy volunteers: a randomized phase I trial.
Peppe, J, Porzio, A, Davidson, DM
British journal of clinical pharmacology. 2008;(1):102-9
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Abstract
AIMS: To evaluate the safety and tolerability of a new oral solution formulation of tolevamer potassium sodium, a nonantibiotic polymer that binds Clostridium difficile toxins A and B. METHODS This phase 1 randomized, double-blind, placebo-controlled study evaluated four doses of tolevamer potassium sodium in 40 healthy volunteers using a sequential dose escalation paradigm and doses of 6, 9, 12 and 15 g day(-1) for 9 days. Within each 10 patient cohort, eight patients received active treatment and two matching placebo. Placebo subjects were pooled to provide eight per arm. All subjects received three times daily dosing on days 2-8 as well as a loading dose (a single dose equal to the total daily dose) either on day 1 or day 9. RESULTS All 40 subjects completed the study per protocol. Treatment-emergent adverse events (TEAEs) were generally mild, transient, and resolved without sequelae. There were no serious AEs or deaths. There was no relationship detected between dose and the incidence of TEAEs, whether drug-related (all gastrointestinal disorders) or not. No clinically significant changes in laboratory parameters, including serum and urinary potassium concentrations, vital signs, and results of physical examination, were observed. A small but statistically significant reduction in 24 h urine potassium excretion was seen in the 15 g day(-1) dose group, and on day 10 in the 6 g day(-1) group. CONCLUSIONS Tolevamer oral solution administered for 9 days at total daily doses up to 15 g, with loading doses of up to 15 g, was generally safe and well-tolerated in healthy volunteers.