阅读说明：本技术 用于血液透析患者中使用的钾结合剂 (Potassium binders for use in hemodialysis patients ) 是由 J·约纳松 N·古斯曼 于 2020-03-12 设计创作，主要内容包括：本发明涉及钾结合剂的用途,这些钾结合剂被配制用来在血液透析患者中以升高的速率从胃肠道去除毒素(例如,钾离子)而不引起不希望的副作用。这些组合物表现出用于长期施用以治疗或预防某些病症如高钾血症的复发或发生所需的特征。(The present invention relates to the use of potassium binders formulated to remove toxins (e.g., potassium ions) from the gastrointestinal tract at an elevated rate without causing undesirable side effects in hemodialysis patients. These compositions exhibit desirable characteristics for long-term administration to treat or prevent the recurrence or occurrence of certain conditions, such as hyperkalemia.)

1. A method for treating hyperkalemia in a hemodialysis patient, the method comprising administering a potassium-binding agent to a patient in need thereof.

2. The method of claim 1, wherein the potassium binder is microporous zirconium silicate.

3. The method of claim 1, wherein the potassium binder is sodium zirconium cyclosilicate.

4. The method of claim 1, wherein the potassium-binding agent is administered on a non-dialysis day.

5. The method of claim 3, wherein the potassium binding agent is administered at a dose of 5 grams.

6. The method of claim 3, wherein the potassium binding agent is administered at a dose of 10 grams.

7. The method of claim 3, wherein the potassium binding agent is administered at a dose of 15 grams.

8. The method of claim 1, wherein the potassium-binding agent is administered on a non-dialysis day.

9. The method of claim 1, wherein the potassium binder is a 2-fluoroacrylate-divinylbenzene-1, 7-octadiene copolymer crosslinked in the form of a salt or an acid.

10. The method of claim 1, wherein the 2-fluoroacrylate-divinylbenzene-1, 7-octadiene copolymer crosslinked in salt or acid form is calcium pertrolem sorbitol.

Technical Field

The present invention relates to the use of potassium binders formulated to remove toxins (e.g., potassium ions) from the gastrointestinal tract at an elevated rate without causing undesirable side effects in hemodialysis patients. These compositions exhibit desirable characteristics for long-term administration to treat or prevent the recurrence or occurrence of certain conditions, such as hyperkalemia.

Background

Acute hyperkalemia is a serious life-threatening condition caused by elevated serum potassium levels. Potassium is a ubiquitous ion involved in many processes in the human body. Potassium is the most abundant intracellular cation and is crucial for many physiological processes, including the maintenance of cellular membrane potential, homeostasis of cell volume, and the transmission of action potentials. Its main dietary sources are vegetables (tomatoes and potatoes), fruits (oranges, bananas) and meat. Normal potassium levels in plasma are between 3.5-5.0mmol/l, with the kidney being the primary regulatory organ for potassium levels. Potassium excretion by the kidney is passive (through the glomeruli) and is actively reabsorbed in the proximal tubule and ascending branches of the henle loop. There is active excretion of potassium in the distal tubules and collecting ducts, both processes being controlled by aldosterone. The increased extracellular potassium levels result in depolarization of the membrane potential of the cell. This depolarization opens some voltage-gated sodium channels, but is insufficient to generate action potentials. After a short transient period, the open sodium channels deactivate and become unreactive, raising the threshold for generating an action potential. This results in damage to the neuromuscular system, the cardiac system and the gastrointestinal organ system, and this damage causes symptoms that can be seen in hyperkalemia. The most alarming is the effect on the cardiac system, where damage to the cardiac conduction can cause fatal cardiac arrhythmias, such as cardiac arrest or ventricular fibrillation. Hyperkalemia represents an acute metabolic emergency that must be corrected immediately due to the possibility of fatal cardiac arrhythmias.

Hyperkalemia develops further when serum potassium is produced in excess (oral intake, tissue breakdown). Voiding failure, which is the most common cause of hyperkalemia, can be hormonal (as in aldosterone deficiency), pharmacological (treatment with ACE inhibitors or angiotensin receptor blockers), or more commonly, due to impaired renal function or advanced heart failure. The most common cause of hyperkalemia is renal insufficiency, and there is a close correlation between the degree of renal failure and serum potassium (S-K) levels. In addition, many different commonly used drugs cause hyperkalemia, such as ACE inhibitors, angiotensin receptor blockers, potassium sparing diuretics (e.g. amiloride, spironolactone), NSAIDs (e.g. ibuprofen, naproxen, celecoxib), heparin, and certain cytotoxic and/or antibiotic drugs (e.g. cyclosporine and trimethoprim). Finally, beta blockers, digoxin or succinylcholine are other well-known causes of hyperkalemia. In addition, hyperkalemia is caused by advanced stages of congestive heart disease, major injury, burns or intravascular hemolysis, such as metabolic acidosis (most commonly as part of diabetic ketoacidosis) can cause hyperkalemia.

Some of the symptoms of hyperkalemia are non-specific and typically include discomfort, palpitations and muscle weakness, or signs of arrhythmia, such as palpitations, alternating rapid and slow heart beats, or dizziness/fainting. Often, however, hyperkalemia is detected during routine screening blood tests for medical disorders or after severe complications have developed (e.g., arrhythmia or sudden death). By S-K measurements, a diagnosis is clearly established.

Treatment depends on S-K levels. In more moderate conditions (S-K between 5mmol/l and 6.5 mmol/l), the resin is bound with potassiumAcute treatment, combined with dietary recommendations (low potassium diet) and possible modifications to medication (if medication causes hyperkalemia) are standard of care; if S-K is higher than 6.5mmol/l or if arrhythmia is present, the urgency for potassium is reduced and close monitoring in a hospital setting is mandatory. The following treatments are typically used following an emergency reduction of potassium:

resins that bind potassium in the intestine and thereby increase defecation, thereby reducing S-K levels. However, becauseIt has been shown to cause ileus and possible hernia. In addition, there is a need for treatment that simultaneously induces diarrhea. These factors have reduced the useAdaptability to treatment.

Partiramer (Patiromer, Veltssa) is a crosslinked polymer of 2-fluoroacrylic acid with divinylbenzene and 1, 7-octadiene; the use of patatimer in the form of its calcium salt and together with sorbitol, such a combination is called patatimer sorbitex calcium.

Sodium zirconium cyclosilicate (Lokelma or SZC) is a microporous ion exchanger of zirconium silicate.

Insulin IV (+ glucose to prevent hypoglycemia) moves potassium into the cells and out of the blood.

Calcium supplement. Calcium does not reduce S-K, but it reduces myocardial excitability and thus stabilizes the myocardium, reducing the risk of arrhythmia.

A bicarbonate salt. Bicarbonate ions will stimulate potassium to exchange for sodium, resulting in stimulation of sodium potassium atpase, dialysis (in severe cases).

The kidney plays a major role in potassium excretion. Patients with End Stage Renal Disease (ESRD) have a reduced renal potassium excretion capacity, which often leads to hyperkalemia (S-K > 5.1 mmol/L). These patients rely on administration of renal replacement therapy (e.g., hemodialysis, including low potassium dialysate as necessary), dietary potassium limitation, and occasional use of oral potassium-binding resins to maintain serum potassium levels within physiological ranges (Clin J Am Soc Nephrol [ J.Ames. Cleroden Nephrol [ J.Clerode ] 11: 90-100, 2016, Clin J Am Soc Nephrol [ J.Valenc. Clerode ] 2: 999-. High serum potassium can lead to ventricular arrhythmias and cardiac death. A recent study showed that S-K > 5.6mmol/L is associated with increased mortality, including all-cause mortality and cardiovascular mortality, in patients with ESRD receiving hemodialysis therapy compared to a reference classification with S-K levels between 4.6mmol/L and 4.99mmol/L (Clin J Am Soc Nephrol [ J. nephrology Association clinical J. USA ] 2: 999-. Furthermore, Sudden Cardiac Death (SCD) is the leading cause of death in hemodialysis patients. In the american kidney data system (USRDS) database, 26.9% of all-cause mortality in widespread dialysis patients between 2009 and 2011 was attributed to cardiac arrest or arrhythmia. The incidence of SCD in hemodialysis patients in 2011 was 49.2 cases/1000 patients-year, which is much higher than the general population (PLoS One [ public science library. integrated ].2015, 10.6 months; 10 (10): e0139886. doi: 10.1371/journal. bone. 0139886).

Hemodialysis patients have high pre-dialysis potassium concentrations. These patients typically receive dialysis treatment on monday, wednesday, and friday. After dialysis, serum K rebounds rapidly and becomes hyperkalemic again before dialysis for the next cycle. Pre-dialysis hyperkalemia and hypokalemic dialysate are associated with increased risk of cardiac arrest, sudden cardiac death and CV mortality.

Hyperkalemia is considered to be an important risk factor for arrhythmias and SCD. This condition is also independently associated with higher short-term risk of hospitalization and emergency visits, as well as higher hospitalization costs (Am J Kidney Dis 70: 21-292017). Therefore, the prevention and treatment of hyperkalemia is of crucial importance in hemodialysis patients.

Currently, the only generally accepted option for treating hyperkalemia in patients with ESRD is dialysis, including low potassium dialysate (hemodialysis or peritoneal dialysis and hemodiafiltration) if necessary. Despite dialysis, the prevalence of hyperkalemia in this population is still high, reaching 62.9 cases/100 patients-month at the end of the long dialysis interval (Am J Nephrol [ J. Kidney disease USA ] 44: 179-186, 2016). In the latter study hyperkalemia was defined as greater than 5.5mmol/L serum potassium before dialysis, and its presence was associated with increased all-cause mortality. Although potassium-binding resins are used in certain cases to treat hyperkalemia in dialysis patients, these agents have not been studied systematically, are not commonly used, and there is no specific indication in this population.

Disclosure of Invention

The disclosure relates to the administration of potassium-binding agents to hemodialysis patients, whereby normotamia is maintained during the dialysis interval.

Drawings

FIG. 1 flow chart of the study

FIG. 2 evaluation protocol-treatment and follow-up phases

FIG. 3 analysis of responder rates

FIG. 4 Effect on Pre-and post-dialysis Potassium concentration

Detailed Description

In one embodiment, the disclosure relates to the administration of a suitable dose of a potassium-binding agent to a hemodialysis patient.

In one embodiment, the disclosure relates to administering a suitable dose of microporous zirconium silicate to a hemodialysis patient.

In one embodiment, the disclosure relates to the administration of a suitable dose of sodium zirconium cyclosilicate to a hemodialysis patient.

In one embodiment, the disclosure relates to the administration of a suitable dose of a 2-fluoroacrylate-divinylbenzene-1, 7-octadiene copolymer crosslinked in salt or acid form to a hemodialysis patient.

In a further embodiment, the disclosure relates to administering a suitable dose of calcium pertrolactirate to a hemodialysis patient.

In further embodiments, the disclosure relates to administering (i.e., on a non-dialysis day) a suitable dose of sodium zirconium cyclosilicate to a hemodialysis patient prior to dialysis.

In one embodiment, the dose of potassium binding agent may be in the range of from 1g to 30g, preferably in the range of from 5g to 15g, more preferably 5 g.

In further embodiments, the dose of potassium binding agent may be in the range of from 1g to 30g, preferably in the range of from 5g to 15g, more preferably 10 g.

In further embodiments, the dose of potassium binding agent may be in the range of from 1g to 30g, preferably in the range of from 10g to 20g, more preferably 15 g.

In a further embodiment, the disclosure relates to administering 5 grams of sodium zirconium cyclosilicate to a hemodialysis patient prior to dialysis (i.e., on a non-dialysis day).

In a further embodiment, the disclosure relates to administering 10 grams of sodium zirconium cyclosilicate to a hemodialysis patient prior to dialysis (i.e., on a non-dialysis day).

In a further embodiment, the disclosure relates to administering 15 grams of sodium zirconium cyclosilicate to a hemodialysis patient prior to dialysis (i.e., on a non-dialysis day).

The use of zirconium silicate or titanium silicate microporous ion exchangers to remove toxic cations and anions from blood or dialysate is described in U.S. Pat. nos. 6,579,460, 6,099,737, 6,332,985, and U.S.2004/0105895, each of which is incorporated herein in its entirety. Additional examples of microporous ion exchangers are found in U.S. patent nos. 6,814,871, 5,891,417, and 5,888,472, each of which is incorporated herein in its entirety.

Certain zirconium silicate compositions may exhibit undesirable effects when used in vivo to remove potassium in the treatment of hyperkalemia. In particular, the inventors of the present invention found that administration of a zirconium silicate molecular sieve composition was associated with mixed leukocyte inflammation, the incidence of minimal acute cystitis, and the observation of unidentified crystals in the renal pelvis and urine, along with an increase in urine pH, in animal studies. These problems are solved by controlling the particle size and sodium content of the zirconium silicate composition. See U.S. patent nos. 8,802,152 and 8,808,750, each of which is incorporated herein in its entirety.

In addition, certain zirconium silicate compositions have had the following problems: crystalline impurities and undesirably low cation exchange capacity. The reduction of more soluble forms of zirconium silicate is important to reduce or eliminate systemic absorption of zirconium or zirconium silicate. This problem is solved by controlling the production conditions in such a way that ZS-8 is substantially eliminated from the composition, resulting in undetectable levels of ZS-8. See U.S. patent No. 8,877,255.

Certain zirconium silicate compositions are useful for long term use, for example, in the treatment of conditions associated with elevated serum potassium levels. The use of zirconium silicate compositions in long-term treatment regimens requires careful control of impurities in the compositions, particularly lead. For example, the FDA sets the acceptance criteria for lead in compositions for extended use to 5 micrograms per day. Certain zirconium silicates produced in commercial quantities using known methods contain about 1ppm to 1.1ppm or more of lead. Even when zirconium silicate is prepared in smaller batches at higher purity, the level of lead is found to be 0.6ppm or more.

Since zirconium silicate therapy utilizes daily doses ranging from 5 grams to 45 grams, a reduction in the level of lead is necessary. Compositions of zirconium silicate having a lead content within the acceptable range required for a daily dose of zirconium silicate are disclosed in US 2017/0151279 a 1.

Sodium zirconium cyclosilicate is a cation exchange composition comprising a zirconium silicate having the formula (I):

A_pM_xZr_1-xSi_nGe_yO_m (I)

wherein

A is potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or a mixture thereof,

m is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+), or a mixture thereof,

"p" has a value of from about 1 to about 20,

"x" has a value from 0 to less than 1,

"n" has a value of from about 0 to about 12,

"y" has a value of from 0 to about 12,

"m" has a value of from about 3 to about 36, and 1. ltoreq. n + y. ltoreq.12,

wherein the composition exhibits a lead content of less than 0.6 ppm. Preferably, the lead content ranges from 0.1ppm to 0.6ppm, more preferably from 0.3ppm to 0.5ppm, and most preferably from 0.3ppm to 0.45 ppm. In one embodiment, the lead content is 0.38 ppm.

In addition to having the desired lead impurity level, the composition may exhibit one or more characteristics that make it desirable as an ion trap for oral ingestion. In one aspect, the zirconium silicate composition may have a potassium exchange capacity in excess of 2.3meq/g, preferably ranging from 2.3meq/g to 3.5meq/g, more preferably ranging from 3.05meq/g and 3.35meq/g, and most preferably about 3.2 meq/g. In one embodiment, 7% of the particles in the composition have a diameter of less than 3 microns. In other embodiments, less than 0.5% of the particles in the composition have a diameter of less than 1 micron. Preferably, the sodium content is below 12% by weight, and more preferably, 9% by weight or less. The zirconium silicate preferably exhibits an XRD diffractogram having two highest peaks occurring at approximately 15.5 and 28.9, with the highest peak occurring at 28.9. The material is preferably ZS-9, or predominantly ZS-9, having a pH ranging from 7 to 9, and a potassium loading of between 2.7 and 3.7mEq/g, and most preferably about 3.5.

Examples of the invention

Phase 3b, multicenter, prospective, concomitant reduction in incidence of pre-dialysis hyperkalemia using Sodium Zirconium Cyclosilicate (SZC) Organic, double-blind, placebo-controlled study

The study was conducted to evaluate the efficacy of sodium zirconium cyclosilicate in treating hyperkalemia in patients receiving hemodialysis. The study was designed to include approximately 180 patients with ESRD who received three maintenance hemodialysis treatments weekly for indications to treat hyperkalemia (fig. 1). The study was a randomized, double-blind study with two treatment groups (SZC or placebo) and included hemodialysis patients who had received dialysis for at least three months and three dialysis treatments per week. The patient must have a hemodialysis access consisting of an arteriovenous fistula, AV graft or a tunneled (permanent) catheter, which is expected to remain in place throughout the study (fig. 2).

The starting dose of SZC would be 5g once daily on a non-dialysis day, and it would be adjusted to a maximum dose of 15g per non-dialysis day to maintain S-K between 4-5mmol/L before dialysis. SZC or placebo will be administered orally on a non-dialysis day for a treatment period of eight weeks. Patients will be randomized (1: 1) to double-blind treatment with SZC or placebo, starting once daily at 5g on a non-dialysis day and titrating during a four week period to achieve and maintain a long dialysis interval (LIDI) before dialysis serum potassium of between 4mmol/L and 5 mmol/L. On the non-dialysis day, the maximum SZC dose was 15g, once a day. Treatment will remain unchanged for an additional four week evaluation period to complete the study for a total of 8 weeks. The primary benefit for patients randomized to SZC is expected to be the maintenance of normotamia during long dialysis intervals, possibly including relief of associated signs and symptoms and improvement in quality of life.

Inclusion criteria

For inclusion in the study, patients should meet the following criteria:

1. informed consent was provided prior to any study specific procedure.

2. At screening visit 1, women or men aged > 18 years. For patients < 20 years of age and enrolled in japan, written informed consent should be obtained for the patient and his legal representative.

3. Hemodialysis (or hemodiafiltration) was received three times a week for treatment of End Stage Renal Disease (ESRD) for at least three months prior to randomization.

4. The patient must have a hemodialysis access consisting of an arteriovenous fistula, AV graft or a tunneled (permanent) catheter, which is expected to remain in place throughout the study.

5. During the screening period, the long dialysis interval after dialysis before S-K > 5.4mmol/L, and one short dialysis interval after dialysis before S-K > 5.0 mmol/L.

6. During the screening, the specified dialysate K concentration is less than or equal to 3 mmol/L.

7. During screening with the recipe (time, dialyzer, blood flow [ Qb ], dialysate flow [ Qd ], and bicarbonate concentration), Qb ≧ 200ml/min and spKt/V ≧ 1.2 (or URR ≧ 63) are maintained under a stable hemodialysis/hemodiafiltration recipe, which is expected to remain unchanged during the study.

8. The heparin dose (if used) must be stable during screening and is expected to be stable during the study.

9. The subject must be receiving dietary recommendations for ESRD patients eligible for treatment with hemodialysis/hemodiafiltration in accordance with local guidelines including dietary potassium restrictions.

Exclusion criteria

Patients should not enter the study if any of the following exclusion criteria are met:

1. participate in the planning and/or implementation of the study.

2. Hemoglobin at screening < 9g/dL (as assessed at visit 1).

3. Lack of compliance (100% compliance is required) with the hemodialysis prescription (both number and duration of treatment) during the period of the first two weeks of screening.

4. Patients treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS, calcium Resonium (sodium)) or pertactin (velssala) within 7 days prior to screening or patients who are expected to require any of these agents during the study.

5. Myocardial infarction, acute coronary syndrome, stroke, seizure or thrombotic/thromboembolic events (e.g., deep vein thrombosis or pulmonary embolism, but not vascular access thrombosis) within 12 weeks prior to randomization.

6. The laboratory diagnosed with hypokalemia (S-K < 3.5mmol/L), hypocalcemia (Ca < 8.2 Mg/dL; for Japan hypocalcemia is defined as albumin-corrected Ca < 8.0Mg/dL), hypomagnesemia (Mg < 1.7Mg/dL) or severe acidosis (16 mEq/L or less for serum bicarbonate) for four weeks prior to randomization.

7. Pseudohyperkalemia secondary to hemolytic specimens (this is not considered a screening failure and sampling or comprehensive screening may be postponed to a later time if applicable).

8. Severe leukocytosis (> 20X 10) during screening⁹/L) or thrombocytosis (. gtoreq.450X 10⁹/L)。

9. Polycythemia (Hb > 14g/dL) was monitored during the screening period.

10. Rhabdomyolysis syndrome was diagnosed during the first four weeks of randomization.

11. Patients with hyperammonemia were treated with lactulose, xifaxan (rifaximin) or other non-absorbable antibiotics within seven days prior to the first dose of study drug.

12. Patients who cannot take oral SZC drug cocktail.

13. The date of live kidney transplantation is scheduled.

14. Patients with a life expectancy of less than six months.

15. A pregnant or lactating female patient.

16. Women with childbearing potential are expected unless contraceptives or abstinence detailed in the protocol is used.

17. Known to be allergic or past allergic to SZC or components thereof.

18. During the last month prior to screening, another clinical study on the study product was engaged.

19. Any medical condition (including active, clinically significant infections that the researcher or sponsor deems may pose a safety risk to the patients in the study) that may confound safety or efficacy assessments and reduce the quality of the data, or may interfere with the participation of the study.

20. There are arrhythmias or conduction defects that require immediate treatment.

21. There was a history of alcohol abuse or drug abuse within two years prior to randomization.

22. Randomized previously in this study.

Evaluation of therapeutic Effect

Serum potassium measurement

Serum potassium levels (S-K) will be measured using an i-STAT device (Point-Of-Care analyzer) and a central laboratory (c-Lab).

For dose titration and therapeutic control purposes, potassium samples will be analyzed locally using an i-STAT device. If hemolysis or other artifacts are suspected based on the reported i-STAT results, the sample can be re-drawn to confirm the results.

Dialysate potassium concentration prescription and potassium levels

For pre-dialysis serum potassium concentrations < 4mmol/L, subsequent adjustments will be made according to locally accepted clinical practice patterns and guided by the clinical judgment of the investigator. For the center of clinical practice to employ a modified prescription dialysate potassium concentration when the pre-dialysis serum potassium concentration is reduced, if the pre-dialysis serum K is below 4mmol/L, the dialysate K concentration should be increased by 0.5mmol/L or 1mmol/L according to the standard of care, for example increasing dialysate K from 1K to 1.5 or 2K, from 2K to 2.5 or 3K, or from 3K to 3.5 or 4K.

SZC or placebo is suspended in 45ml water and administered orally on a non-dialysis day for a treatment period of eight weeks. The initial SZC dose will be 5g once daily and can be adjusted to a maximum dose of 15g per non-dialysis day to maintain the pre-dialysis S-K between 4-5 mmol/L.

All dose adjustments will be based on pre-dialysis S-K values measured by i-STAT.

The dialysis prescription will be managed according to local clinical model practices.

During the first four weeks of the treatment period, the SZC dose should be adjusted (once weekly dose) if the pre-dialysis potassium value after a long dialysis interval is > 5.0 mmol/L. For patients taking 5g on non-dialysis days, the dose should be increased to 10g on non-dialysis days. For patients taking 10g, the dose should be increased to 15g on the non-dialysis day.

During the first four weeks of the treatment period, serum potassium concentrations should be assessed both before and after dialysis.

For pre-dialysis serum potassium concentrations < 4mmol/L, subsequent adjustments will be made according to locally accepted clinical practice patterns and guided by the clinical judgment of the investigator.

For sites that employ clinical practice of modifying the prescribed dialysate potassium concentration when the pre-dialysis serum potassium concentration is reduced, if the pre-dialysis S-K is below 4mmol/L, the dialysate K concentration should be increased by 0.5mmol/L or 1mmol/L according to the standard of care, for example increasing dialysate K from 1K to 1.5 or 2K, from 2K to 2.5 or 3K, or from 3K to 3.5 or 4K. If the dialysate K concentration cannot be increased further (e.g. the patient has used a 4K dialysate bath), the dose of SZC can be reduced by 5g or suspended if the patient is already taking a minimum dose (5 g).

For locations where local clinical practice does not include increasing dialysate K concentration when pre-dialysis serum K is decreasing, the dose of SZC can be reduced by 5g or paused if the patient is already taking a minimum dose (5 g).

If the dose of SZC has been reduced or paused during the treatment period (first four weeks) and the pre-dialysis potassium value is higher than 5.0mmol/L after the next long dialysis interval, the dose of 5g should be increased as much as possible or SZC 5g restarted if it has been paused.

After the first four weeks, no further adjustments of the SZC dose or dialysate potassium concentration should be made unless the primary investigator judges there is an urgent medical need to treat abnormal serum potassium concentrations (i.e., severe hyperkalemia or hypokalemia with clinical manifestations). If such an event occurs, appropriate dose adjustments (increases or decreases) of the SZC can be made while recording the event. In the case of hyperkalemia whose clinical manifestations are considered to require urgent treatment, remedial treatment, defined as any intervention consistent with the local mode of practice of lowering serum K, may be administered, followed by appropriate SZC dose adjustments and convenient event logging. During the last four weeks of the treatment period, the evaluation of serum potassium concentrations both before and after dialysis will be continued. It is recommended to keep the diet regimen unchanged for the duration of the study.

Results

97 patients were randomized to SZC group and 99 patients were randomized to placebo group. All randomized patients, except one in the SZC group, received treatment. The primary outcome measure of this study was defined as the proportion of patients who maintained pre-dialysis serum potassium between 4.0-5.0mmol/L after a long dialysis interval (LIDI) during the evaluation period (4 weeks post) in 3 of 4 dialysis treatments and who received no remedial treatment. Analysis was performed using the ITT (intent to treat) principle. All randomized patients were under analysis, even those who did not receive treatment. This means, for example, that differences in treatment interruption between treatment groups may have an effect on the outcome. Patients were included as non-responders even though they had data missing (fig. 3).

After a dose adjustment period (initial dose of 5g), 37%, 43% and 19% of patients received 5g, 10g and 15g of SZC, respectively. One patient titrated down to 0 g.

The number of adverse events in patients was balanced between the treatment groups, 40 in SZC group and 46 in placebo group. Of these, 7 in the SZC group and 8 in the placebo group were considered serious adverse events, including one death in the SZC group (which was judged to be unrelated to the study product). There were 10 pre-dialysis hypokalemia patients (defined as serum K < 3.5mmol/L), five per treatment group.

The reduction in mean serum K before dialysis during dose adjustment in the SCZ group was stable during the evaluation period and increased after the follow-up period. In the placebo group, the pre-dialysis mean serum K was stable during the treatment period. Mean serum K after dialysis showed a similar pattern, but was less pronounced (fig. 4).

The mean K changes were smaller in SZC group compared to placebo group throughout the evaluation period starting from visit 9. The mean K change in the placebo group was about 1.9 mmol/L. Between visit 9 and visit 15, the average K in the SZC group changed to 1.4-1.5 mmol/L.

Throughout the evaluation period, starting from visit 8, the mean K-gradient was smaller in SZC group compared to placebo group. The mean K gradient in the placebo group was about 3.5 mmol/L. The average K gradient in the SZC group was 2.7-2.9mmol/L between visit 8 and visit 15.

The proportion of responders in SZC was statistically significantly higher compared to placebo, 41.2% in SZC group and 1.0% in placebo group. (FIG. 4: bars represent 2 standard deviations (mean)). Treatment with SZC did not pose a safety problem.