Clinical trial NCT03127644: ZS Ph2/3 Dose-response Study in Japan
Official title: A Phase 2/3 Multicenter, Dose-response Study to Assess Efficacy and Safety of ZS (Sodium Zirconium Cyclosilicate), in Japanese Patients With Hyperkalemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hyperkalemia
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-04-25
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To assess efficacy of 5 g three times daily (TID) and 10 g TID ZS versus placebo in Japanese patients with hyperkalemia (serum potassium \[S-K\] ≥ 5.1 mmol/L and ≤ 6.5 mmol/L).

Detailed description: Patients not receiving any therapy for hyperkalemia and with 2 consecutive i-STAT potassium values of ≥ 5.1 mmol/L and ≤ 6.5 mmol/L will be enrolled and randomized 1:1:1 to receive ZS 5 g, ZS 10 g, or placebo TID for 48 hours.

Throughout the study most potassium values will be measured at fasting before taking study drug. Nothing should be taken by mouth except water, coffee or tea, with or without milk and/or sugar, and essential medications, prior to the blood collection for a minimum of 8 hours. Potassium level should be determined by both i-STAT and the Central Laboratory on all occasions. Treatment decisions (eg, stopping rules) will be made based on i-STAT potassium values, as these provide clinical sites with a real-time measurement. Statistical analyses on the study data will in principle be based on S-K values as measured by the central laboratory.

Safety and tolerability will be assessed on an ongoing basis. Standard study assessments including blood potassium, clinical chemistry (including calcium, magnesium, sodium, phosphate, creatinine, bicarbonate, and blood urea nitrogen \[BUN\]) and hematology parameters, urinalysis, vital signs, physical examinations, and electrocardiograms (ECGs) will be assessed during the study at the time points specified in the assessments schedule. All women of childbearing potential will have a urine pregnancy test prior to enrollment and at their End of Study (EOS) visit.

Stopping rules will be implemented to ensure subjects discontinue the study treatment and receive alternative therapy in case of significant hyperkalemia, hypokalemia, or significant cardiac arrhythmias.

Eligibility criteria: Inclusion Criteria:

* Provision of informed consent prior to any study specific procedures.
* Patients aged ≥18. For patients aged \<20 years, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
* Two consecutive i-STAT potassium values, measured 60 (± 10) minutes apart, both values should be ≥ 5.1 mmol/L and ≤ 6.5 mmol/L and measured within 1 day before the first dose of study drug on Study Day 1.
* Ability to have repeated blood draws or effective venous catheterization.
* Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.

Exclusion Criteria:

* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
* Cause or symptoms of pseudohyperkalemia, such as

  1. hemolyzed blood specimen due to excessive fist clenching to make veins prominent
  2. hemolyzed blood specimen due to difficult or traumatic venepuncture
  3. history of severe leukocytosis or thrombocytosis
* Patients treated with lactulose, rifaximin, or other non-absorbed antibiotics for hyperammonemia within 7 days prior to first dose of study drug on Study Day 1
* Patients treated with resins (such as sevelamer hydrochloride, sodium polystyrene sulfonate \[SPS; e.g. Kayexalate®\] or calcium polystyrene sulfonate \[CPS\]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug
* Patients with a life expectancy of less than 3 months
* Patients who are severely physically or mentally incapacitated and who, in the opinion of investigator, are unable to perform the patients' tasks associated with the protocol
* Female patients who are pregnant, lactating, or planning to become pregnant
* Patients who have an active or history of diabetic ketoacidosis
* Presence of any condition which, in the opinion of the investigator, places the patient 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
* Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry
* Patients with cardiac arrhythmias that require immediate treatment
* Patients on dialysis

Primary outcomes:
measure: Exponential Rate of Change in Serum Potassium (S-K) Values During the Initial 48 Hours of Study Drug Treatment
timeFrame: From 0 to 48 hours.
Secondary outcomes:
measure: Percentage of Patients Who Achieved Normokalaemia at 48 Hours
timeFrame: At 48 hours.
measure: Exponential Rate of Change in S-K Values During the Initial 24 Hours of Study Drug Treatment
timeFrame: From 0 to 24 hours.
measure: Percentage of Patients Who Achieved Normokalaemia at 24 Hours
timeFrame: At 24 hours.
measure: Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point
timeFrame: From baseline to end of study (9 days).
measure: Mean Change From Baseline in S-K Values at All Measured Time Intervals
timeFrame: From baseline to end of study (9 days).
measure: Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals
timeFrame: From baseline to end of study (9 days).
measure: Time to Normalisation in S-K Values
timeFrame: From 0 to 48 hours.
measure: Time to a Decrease in S-K Levels of 0.5 mmol/L
timeFrame: From 0 to 48 hours.
Other outcomes:
Locations:
city: Chiba-shi
country: Japan
facility: Research Site
city: Chiba-shi
country: Japan
facility: Research Site
city: Hanyu-shi
country: Japan
facility: Research Site
city: Higashiibaraki-gun
country: Japan
facility: Research Site
city: Hitachinaka-shi
country: Japan
facility: Research Site
city: Ina-shi
country: Japan
facility: Research Site
city: Kagoshima-shi
country: Japan
facility: Research Site
city: Kahoku-gun
country: Japan
facility: Research Site
city: Kamakura-shi
country: Japan
facility: Research Site
city: Kanazawa-shi
country: Japan
facility: Research Site
city: Kasugai-shi
country: Japan
facility: Research Site
city: Kawachinagano-shi
country: Japan
facility: Research Site
city: Kawasaki-shi
country: Japan
facility: Research Site
city: Kitakyushu-shi
country: Japan
facility: Research Site
city: Koga-shi
country: Japan
facility: Research Site
city: Kusatsu-shi
country: Japan
facility: Research Site
city: Matsudo-shi
country: Japan
facility: Research Site
city: Matsuyama-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Naka-shi
country: Japan
facility: Research Site
city: Omura-shi
country: Japan
facility: Research Site
city: Shimajiri-gun
country: Japan
facility: Research Site
city: Shizuoka-shi
country: Japan
facility: Research Site
city: Yao-shi
country: Japan
facility: Research Site
city: Yotsukaido-shi
country: Japan
facility: Research Site
Study officials:
References:
citation: Kashihara N, Nishio T, Osonoi T, Saka Y, Imasawa T, Ohtake T, Mizuno H, Shibagaki Y, Kim H, Yajima T, Sarai N. Correction of serum potassium with sodium zirconium cyclosilicate in Japanese patients with hyperkalemia: a randomized, dose-response, phase 2/3 study. Clin Exp Nephrol. 2020 Dec;24(12):1144-1153. doi: 10.1007/s10157-020-01937-1. Epub 2020 Aug 10.