Multicenter, Two-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-Controlled Study of Safety and Efficacy of Microporous, Fractionated, Protonated Zirconium Silicate in Mild to Moderate Hyperkalemia
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 754
- 试验地点
- 42
- 主要终点
- Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment.
研究概览
简要总结
Acute Phase: It is hypothesized that ZS (zirconium silicate) is more effective than placebo control (alternative hypothesis) in lowering S-K levels in subjects with S-K between 5.0 - 6.5 mmol/l versus no difference between ZS and placebo control (null hypothesis).
Subacute Phase (randomized withdrawal): It is hypothesized that ZS once daily is more effective than placebo control (alternative hypotheses) in maintaining normokalemic levels (3.5 - 4.9 mmol/l) among subjects completing the Acute Phase versus no difference between each ZS dose and respective placebo controls (null hypotheses).
详细描述
A total of 750 subjects with mild to moderate hyperkalemia (i- STAT potassium levels between 5.0-6.5 mmol/l, inclusive) will be enrolled in the study where they, in a double-blind fashion, will be randomized 1:1:1:1:1 to receive one of four (4) doses of ZS (1.25g, 2.5g, 5g, and 10g) or placebo control, administered 3 times daily (tid) with meals for the initial 48 hours (Acute Phase), followed by a Subacute Phase (randomized withdrawal) during which patients treated with active doses in the Acute Phase, who achieve normokalemia (i-STAT potassium values 3.5 to 4.9 mmol/l, inclusive) will be randomized to 12 days of subacute, once a day (qd) dosing. There will be a one-time randomization to assign the Acute Phase treatment and the Subacute Phase treatment. The Subacute Phase will include subjects who became normokalemic on active drug and those who became normokalemic on placebo. The former will be randomized in a 1:1 ratio between the same dose of ZS they received during the acute phase but only administered once a day (qd) or placebo, qd. Subjects on placebo during the Acute Phase who are normokalemic in the morning of Study Day 3, will be randomized to receive either 1.25 or 2.5 g ZS, qd as Subacute Phase treatment.
Safety and tolerability will be assessed on an ongoing basis by an Independent Data Safety Monitoring Board (DSMB). Each active dose group will consist of 150 patients per treatment group including the placebo control group for a total of 750 patients; the 1:1:1:1:1 allocation helps to optimize the multiple active dose comparisons to the respective placebo controls for the Subacute Phase.
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.
- •Mean i-STAT potassium values between 5.0 - 6.5 mmol/l inclusive, at screening (Study Day 0).
- •Ability to have repeated blood draws or effective venous catheterization.
- •Women of childbearing potential must be practicing a highly effective method of birth control.
排除标准
- •Pseudohyperkalemia signs and symptoms, such as excessive fist clinching hemolyzed blood specimen, severe leukocytosis or thrombocytosis.
- •Subjects treated with lactulose, xifaxan or other nonabsorbed antibiotics for hyperammonemia within the last 7 days.
- •Subjects treated with resins (such as Sevelamer acetate or Sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), calcium acetate, calcium carbonate, or lanthanum carbonate, within the last 7 days.
- •Subjects with a life expectancy of less than 3 months.
- •Subjects who are HIV positive.
- •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 Ketoacidosis/Acidemia.
- •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.
- •Previous treatment with ZS
- •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.
- •Insulin-dependent diabetes mellitus
- •Subjects on dialysis
研究组 & 干预措施
Zirconium silicate (acute phase)
Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered 3 times (tid) daily with meals for 48 hours.
干预措施: Zirconium silicate (acute phase) (Drug)
Placebo (acute phase)
Placebo ( silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals.
干预措施: Placebo (acute phase) (Drug)
Zirconium silicate (subacute phase)
Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered once a day prior to the morning meal for 12 days.
干预措施: Zirconium silicate (subacute phase) (Drug)
Placebo (subacute phase)
Placebo (silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered once a day (qd) prior to the morning meal for 12 days.
干预措施: Placebo ( subacute phase) (Drug)
结局指标
主要结局
Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment.
时间窗: Through 48 hours acute phase
Exponential Rate of Change in S-K Levels in the Subacute Phase.
时间窗: Through 12 days subacute phase (Day 3 through Day 15)
次要结局
- Mean Change From Baseline in S-K at All Time Points Acute Phase(Through 48 hours acute phase. In particular, at Baseline; 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3.)
- Percentage of Subjects Within Each Treatment Group Who Retained Normal S-K Values at End of Subacute Phase(Through 18 days of subacute phase (12 days treatment, 6 days follow-up))
- Mean Change From Subacute Baseline in Serum Potassium at All Time Points.(Through 18 days of subacute phase (12 days treatment, 6 days follow-up))
- Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment(Through 48 hours acute phase)
- Mean Percent Change From Baseline in S-K Change at All Time Points Acute Phase(Through 48 hours acute phase. In particular, 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3.)
- Time Subjects Remain Normokalemic (Subacute Phase)(Through 18 days (12 days treatment, 6 days follow-up) of subacute phase)
- Mean Percent Change From Subacute Baseline in Serum Potassium at All Time Points.(Through 18 days of subacute phase (12 days treatment, 6 days follow-up))