Correction of serum potassium with sodium zirconium cyclosilicate in Japanese patients with hyperkalemia: a randomized, dose–response, phase 2/3 study

Abstract Background Sodium zirconium cyclosilicate (SZC) is an oral potassium binder approved to treat hyperkalemia in adults in a number of countries, including Japan. Methods This phase 2/3, randomized, double-blind, placebo-controlled, dose–response study (ClinicalTrials.gov: NCT03127644) was designed to determine the efficacy and safety of SZC in Japanese adults with hyperkalemia. Patients with serum potassium (sK+) concentrations ≥ 5.1– ≤ 6.5 mmol/L were randomized 1:1:1 to SZC 5 g, SZC 10 g, or placebo three times daily for 48 h (six doses total). The primary efficacy endpoint was the exponential rate of change in sK+ over 48 h. The proportion of patients with normokalemia (sK+ 3.5–5.0 mmol/L) at 48 h and adverse events (AEs) were also evaluated. Results Overall, 103 patients (mean age, 73.2 years; range 50–89 years) received SZC 5 g (n = 34), SZC 10 g (n = 36), or placebo (n = 33). The exponential rate of sK+ change from 0 to 48 h versus placebo was − 0.00261 (SZC 5 g) and – 0.00496 (SZC 10 g; both P < 0.0001). At 48 h, the proportions of patients with normokalemia were 85.3%, 91.7%, and 15.2% with SZC 5 g, SZC 10 g, and placebo, respectively. No serious AEs were reported. Hypokalemia (sK+ < 3.5 mmol/L) occurred in two patients in the SZC 10 g group; normokalemia was re-established within 6 days and no treatment-related AEs were reported. Conclusion SZC is effective and well tolerated in Japanese patients with hyperkalemia.

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Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose–response study and open-label extension study

Clinical and Experimental Nephrology ◽

10.1007/s10157-020-01963-z ◽

2020 ◽

Author(s):

Takashi Wada ◽

Masaya Inagaki ◽

Toru Yoshinari ◽

Ryuji Terata ◽

Naoko Totsuka ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Dose Response ◽

Serum Potassium ◽

Extension Study ◽

Phase 2 ◽

Open Label ◽

Double Blind ◽

Double Blind Placebo ◽

Remission Rates ◽

Dose Response Study

Abstract Background We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). Methods The study had two parts: a dose–response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). Results In the dose–response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. Conclusion The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. Clinical trial registration NCT02517320 (dose–response study) and NCT02676401 (extension study)

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FP008ACHIEVEMENT OF NORMAL SERUM POTASSIUM WITH SODIUM ZIRCONIUM CYCLOSILICATE (ZS-9) IN A SUBGROUP OF PATIENTS WITH STAGE 4/5 CHRONIC KIDNEY DISEASE AND BASELINE POTASSIUM ≥5.5 MMOL/L FROM THE PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED HARMONIZE STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfv165.08 ◽

2015 ◽

Vol 30 (suppl_3) ◽

pp. iii68-iii68

Author(s):

Simon D. Roger ◽

Angel de Francisco ◽

Henrik Rasmussen ◽

Philip Lavin ◽

Bhupinder Singh ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Serum Potassium ◽

Normal Serum ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

Sodium Zirconium ◽

Stage 4 ◽

Sodium Zirconium Cyclosilicate

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A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia

Journal of the American Society of Nephrology ◽

10.1681/asn.2019050450 ◽

2019 ◽

Vol 30 (9) ◽

pp. 1723-1733 ◽

Cited By ~ 26

Author(s):

Steven Fishbane ◽

Martin Ford ◽

Masafumi Fukagawa ◽

Kieran McCafferty ◽

Anjay Rastogi ◽

...

Keyword(s):

Serum Potassium ◽

Rescue Therapy ◽

Controlled Study ◽

Serious Adverse Events ◽

Double Blind ◽

Double Blind Placebo ◽

Interdialytic Weight Gain ◽

Sodium Zirconium ◽

Efficacy Outcome ◽

Sodium Zirconium Cyclosilicate

BackgroundPatients with ESRD have minimal renal potassium excretion and, despite hemodialysis, often have persistent predialysis hyperkalemia. The DIALIZE study (NCT03303521) evaluated sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in hemodialysis patients.MethodsIn the DIALIZE study, a double-blind, placebo-controlled, phase 3b multicenter study, we randomized adults with ESRD who were managed by three-times weekly hemodialysis and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on non-dialysis days, and titrated towards maintaining normokalemia over 4 weeks, in 5 g increments to a maximum of 15 g. The primary efficacy outcome was proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0–5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval and did not require urgent rescue therapy to reduce serum potassium.ResultsIn total, 196 patients (mean [standard deviation (SD)] age =58.1 [13.7] years old) were randomized to sodium zirconium cyclosilicate or placebo. Of 97 patients receiving sodium zirconium cyclosilicate, 41.2% met the primary end point and were deemed treatment responders compared with 1.0% of 99 patients receiving placebo (P<0.001). Rescue therapy to reduce serum potassium during the treatment period was required by 2.1% of patients taking sodium zirconium cyclosilicate versus 5.1% taking placebo. Serious adverse events occurred in 7% and 8% of patients in sodium zirconium cyclosilicate and placebo groups, respectively. The two groups displayed comparable interdialytic weight gain. There were few episodes of hypokalemia.ConclusionsSodium zirconium cyclosilicate is an effective and well-tolerated treatment for predialysis hyperkalemia in patients with ESRD undergoing adequate hemodialysis.

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Faculty Opinions recommendation of Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725515440.793511074 ◽

2015 ◽

Author(s):

WH Wilson Tang

Keyword(s):

Heart Failure ◽

Serum Potassium ◽

Controlled Trial ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

Heart Failure Patients ◽

Sodium Zirconium ◽

Sodium Zirconium Cyclosilicate

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FP010MAINTENANCE OF NORMAL SERUM POTASSIUM WITH SODIUM ZIRCONIUM CYCLOSILICATE (ZS-9) IN SUBGROUP OF PATIENTS WITH HISTORY OF CHRONIC KIDNEY DISEASE AND ON RAAS INHIBITORS FROM THE PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED HARMONIZE STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfv165.10 ◽

2015 ◽

Vol 30 (suppl_3) ◽

pp. iii69-iii69 ◽

Cited By ~ 1

Author(s):

David Packham ◽

Henrik Rasmussen ◽

Philip Lavin ◽

Bhupinder Singh ◽

Alex Yang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Serum Potassium ◽

Normal Serum ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

Sodium Zirconium ◽

History Of ◽

Sodium Zirconium Cyclosilicate

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Maintenance of serum potassium with sodium zirconium cyclosilicate ( ZS ‐9) in heart failure patients: results from a phase 3 randomized, double‐blind, placebo‐controlled trial

European Journal of Heart Failure ◽

10.1002/ejhf.300 ◽

2015 ◽

Vol 17 (10) ◽

pp. 1050-1056 ◽

Cited By ~ 74

Author(s):

Stefan D. Anker ◽

Mikhail Kosiborod ◽

Faiez Zannad ◽

Ileana L. Piña ◽

Peter A. McCullough ◽

...

Keyword(s):

Heart Failure ◽

Serum Potassium ◽

Controlled Trial ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

Heart Failure Patients ◽

Sodium Zirconium ◽

Sodium Zirconium Cyclosilicate

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Faculty Opinions recommendation of Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725949928.793558766 ◽

2019 ◽

Author(s):

Sakae Tanaka

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Trial ◽

Phase Ii ◽

Dose Response ◽

Bone Erosion ◽

Japanese Patients ◽

Inhibitory Effect ◽

Double Blind ◽

Double Blind Placebo ◽

Dose Response Study

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Zolmitriptan is Effective and Well Tolerated in Japanese Patients with Migraine: A Dose-Response Study

Cephalalgia ◽

10.1046/j.1468-2982.2002.00377.x ◽

2002 ◽

Vol 22 (5) ◽

pp. 376-383 ◽

Cited By ~ 12

Author(s):

F Sakai ◽

M Iwata ◽

K Tashiro ◽

Y Itoyama ◽

S Tsuji ◽

...

Keyword(s):

Dose Response ◽

Optimal Dose ◽

Japanese Patients ◽

Similar Efficacy ◽

Controlled Study ◽

Response Relationship ◽

Dose Response Relationship ◽

Double Blind ◽

Primary Endpoints ◽

Dose Response Study

This phase II study investigated the efficacy, tolerability and dose-response relationship of oral zolmitriptan in the treatment of a single migraine attack in Japanese patients. A bridging analysis then assessed the validity of extrapolating western clinical data to these Japanese patients. In this multicentre, randomized, double-blind, placebo-controlled study, patients received a single dose of placebo or zolmitriptan 1, 2.5 or 5 mg. The primary endpoints were 2-h headache response and the tolerability of zolmitriptan. A statistically significant dose-response relationship was observed for the 2-h headache response ( P = 0.003). The 2.5 mg group had significantly greater 2-h headache response than the placebo group ( P = 0.032). The adverse event profile was similar to that reported in western patients, and no adverse events unique to the Japanese population were observed. The bridging analysis report confirmed similar efficacy and tolerability of zolmitriptan in Japanese and western populations. In the Japanese patients, the estimated response rates were 34.3%, 45.2%, 57.7% and 66.2% for placebo, and zolmitriptan 1, 2.5 and 5 mg, respectively, while in the western population the corresponding rates were 39.9%, 49.6%, 61.2% and 71.7%. Zolmitriptan is effective and well tolerated in the acute treatment of migraine in Japanese patients. The optimal dose was 2.5 mg, although the 5 mg dose may provide further benefit for some patients. The bridging analysis supports extrapolation of data from western to Japanese patients.

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A Dose-Response Study of Xipamid in Hypertension Used in Combination with other Anti-Hypertensive Drugs

Journal of International Medical Research ◽

10.1177/030006057500300606 ◽

1975 ◽

Vol 3 (6) ◽

pp. 389-394 ◽

Cited By ~ 12

Author(s):

P S Davies ◽

B N C Prichard

Keyword(s):

Blood Pressure ◽

Dose Response ◽

Serum Potassium ◽

Double Blind Study ◽

Normal Range ◽

Double Blind ◽

The Difference ◽

Diuretic Agents ◽

Hypertensive Drug ◽

Dose Response Study

Xipamid has been found to exert an effective anti-hypertensive effect in combination with methyldopa ( four patients), propranolol ( five patients), methyldopa and propranolol ( one patient) and bethanidine ( one patient), also bethanidine and propranolol ( two patients). A double-blind study was performed in ten patients and xipamid 40 mg and 20 mg produced a significant fall in blood pressure, but the difference in effect between the two dosages was insignificant. Xipamid produced a fall in serum potassium below the normal range in half the patients. Xipamid is an effective anti-hypertensive drug that exerts an additive effect with other anti-hypertensive drugs in common with many other diuretic agents.

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