Multicenter, Multi-phase, Multi-dose, Prospective, Double-blind, Placebo-controlled, Maintenance Study of Safety and Efficacy of ZS (Microporous, Fractionated, Protonated Zirconium Silicate) in Hyperkalemia.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 258
- 主要终点
- Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population).
研究概览
简要总结
It is hypothesized that ZS is more effective than placebo control (alternative hypothesis) in maintaining mean double-blind randomized maintenance phase (DBRMP) Day 8-29 serum potassium levels (3.5 - 5.0 mmol/l, inclusive) among hyperkalemic subjects in whom normokalemia was established during the open-label acute phase versus no difference between each ZS dose (highest to lowest) versus placebo control (null hypothesis).
详细描述
Approximately 275 subjects with hyperkalemia (two consecutive i-STAT potassium levels ≥ 5.1 mmol/l, taken 60 minutes apart at baseline) will be enrolled in the Open-label Acute Phase to provide 232 subjects in the Double Blind Randomized Maintenance Phase.
Initially all subjects will receive open-label ZS at a dose of 10g three times a day (tid) for 48 hours (AP). Subjects who achieve normokalemia (i-STAT potassium values between 3.5 to 5.0 mmol/l, inclusive) on the morning of Study Day 3 (after 6 doses of 10g ZS) will then, in a double-blind fashion, be randomized 4:4:4:7 to receive one of three doses of ZS (5g, 10g or 15g) or placebo control, qd for the following 28 days (DBRMP).
Safety and tolerability will be assessed on an ongoing basis by an Independent Data Monitoring Committee (iDMC). Each active dose group in the DBRMP will consist of 49 subjects and the placebo control group will consist of 85 subjects for a total of 232 subjects to detect a 0.6 effect size difference between each ZS dose (from highest to lowest) and placebo control; the 4:4:4:7 allocation optimizes the multiple comparisons to the placebo control for the DBRMP.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of written informed consent.
- •Over 18 years of age.
- •Two consecutive i-STAT potassium values, measured 60-minutes apart, both ≥5.1 mmol/l and measured within 1 day of the first ZS dose on AP Study Day
- •Ability to have repeated blood draws or effective venous catheterization.
- •Women of childbearing potential must be using two forms of medically acceptable contraception (at least one barrier method) and have a negative pregnancy test at AP Study Day
- •Women who are surgically sterile or those who are post-menopausal for at least 2 years are not considered to be of childbearing potential.
排除标准
- •Pseudohyperkalemia signs and symptoms, such as excessive fist clenching hemolyzed blood specimen, history of severe leukocytosis or thrombocytosis.
- •Subjects treated with lactulose, Xifaxan or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug.
- •Subjects treated with resins (such as sevelamer acetate or sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug.
- •Subjects with a life expectancy of less than 3 months.
- •Subjects who are severely physically or mentally incapacitated and who in the opinion of investigator are unable to perform the subjects' tasks associated with the protocol.
- •Women who are pregnant, lactating, or planning to become pregnant.
- •Subjects with diabetic ketoacidosis.
- •Presence of any condition which, in the opinion of the investigator, places the subject at undue risk or potentially jeopardizes the quality of the data to be generated.
- •Known hypersensitivity or previous anaphylaxis to ZS or to components thereof.
- •Randomization into the previous ZS-002 or ZS-003 studies.
- •Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry.
- •Subjects with cardiac arrhythmias that require immediate treatment.
- •Subjects on dialysis.
研究组 & 干预措施
Sodium zirconium cyclosilicate 10 g three times daily
Sodium zirconium cyclosilicate 10 g three times daily for 48 hours (acute phase)
干预措施: Sodium zirconium cyclosilicate (Drug)
Placebo once daily
Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days.
干预措施: Placebo (Drug)
Sodium zirconium cyclosilicate 5 g once daily
Sodium zirconium cyclosilicate (ZS) 5 g once daily for 28 days (maintenance phase)
干预措施: Sodium zirconium cyclosilicate (Drug)
Sodium zirconium cyclosilicate 10 g once daily
Sodium zirconium cyclosilicate (ZS) 10 g once daily for 28 days (maintenance phase)
干预措施: Sodium zirconium cyclosilicate (Drug)
Sodium zirconium cyclosilicate 15 g once daily
Sodium zirconium cyclosilicate (ZS) 15 g once daily for 28 days (maintenance phase)
干预措施: Sodium zirconium cyclosilicate (Drug)
结局指标
主要结局
Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population).
时间窗: 22 Days; Maintenance Phase Days 8 - 29, inclusive.
The least squares means (LSMeans) are dervied from a mixed effects model of serial log transformed S-K values between Days 8 and 29 with patients as a random effect and the following fixed effects terms: MP treatment group; AP baseline eGFR; AP and MP baseline S-K levels, age categories (\<55, 55-64, \>= 65 years); and binary indicators for RAAS inhibitors use, CKD, CHF, and DM. The LSmeans estimate obtained from the above model is back-transformed and presented as the lsmeans of all available S-K values during the Maintenance phase study Days 8 to 29.
次要结局
- Mean Percent Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit, Inclusive .(Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.)
- Proportion of Subjects Who Achieve Normokalemia During the Acute Phase at 24 and 48 Hours After Start of Dosing(Through 48 hours acute phase)
- Mean Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit .(Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.)
- Mean Percent Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.(Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.)
- The Number of Normokalemic Days Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT).(22 days; Maintenance Phase Day 8 - 29, inclusive.)
- Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L)(Maintenance Phase baseline to maintenance Phase Study Day 29/Exit.)
- Proportion of Subjects Who Remained Normokalemic During Maintenance Phase(Maintenance Phase Study Days 1, 2, 5, 8, 12, 15, 19, 22, 26, 29, and 35, inclusive.)
- Median Time to Relapse in S-K Values(Maintenance phase Study Day 1 to Study Day 29/Exit.)
- Exponential Rate of Change in S-K Values During the Acute Phase at 24 Hours and 48 Hours of Study Drug Treatment.(Acute Phase 24 hours and Acute Phase 48 hours.)
- Mean Percent Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.(All measured time intervals post dose during the Acute Phase.)
- Mean Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.(All measured time intervals post dose during the Acute Phase.)
- Mean Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.(Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.)
- Mean S-K Intra-subject Standard Deviation Calculated Among Subjects With ≥ 2 Values on or After Maintenance Phase Study Day 8(22 days; Maintenance Phase Day 8 - 29)
- Median Time to Normalization (3.50-5.0 mmol/L) in S-K Levels in the 48 Hours of Initial Treatment(Through 48 hours acute phase)