A Study to Investigate the Safety and Efficacy of ZS in Patients With Hyperkalemia (HARMONIZE GL)

A Phase 3 Multicenter, Prospective, Randomized, Double-blind, Placebo-controlled Study to Investigate the Safety and Efficacy of ZS, in Patients With Hyperkalemia-HARMONIZE Global

To evaluate the efficacy of two different doses (5 and 10 g) of ZS orally administered once daily (qd) vs placebo in maintaining normokalemia in initially hyperkalemic patients having achieved normokalemia following two days of initial ZS therapy (10g TID).

Study Overview

• Status: Completed
• Conditions: Hyperkalemia
• Intervention / Treatment: Drug: Sodium Zirconium Cyclosilicate (ZS) 5g; Drug: Sodium Zirconium Cyclosilicate (ZS) 10g; Drug: Sodium Zirconium Cyclosilicate (ZS) 10g; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 267
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Chiba-shi, Japan, 260-8712
    • Research Site
  • Hanyu-shi, Japan, 348-8505
    • Research Site
  • Hitachinaka-shi, Japan, 312-0057
    • Research Site
  • Ina-shi, Japan, 396-8555
    • Research Site
  • Kanazawa-shi, Japan, 920-8650
    • Research Site
  • Koga-shi, Japan, 306-0041
    • Research Site
  • Matsudo-shi, Japan, 271-0077
    • Research Site
  • Nagoya-shi, Japan, 457-8511
    • Research Site
  • Nagoya-shi, Japan, 462-0802
    • Research Site
  • Shimajiri-gun, Japan, 901-0493
    • Research Site
  • Shizuoka-shi, Japan, 421-0117
    • Research Site
  • Toride-shi, Japan, 302-0022
    • Research Site
  • Toyohashi-shi, Japan, 441-8570
    • Research Site
  • Yao-shi, Japan, 581-0011
    • Research Site
• Korea, Republic of
  • Anyang-si, Korea, Republic of, 14068
    • Research Site
  • Bucheon-si, Korea, Republic of, 14754
    • Research Site
  • Bucheon-si, Korea, Republic of, 14647
    • Research Site
  • Busan, Korea, Republic of, 49241
    • Research Site
  • Cheongju-si, Korea, Republic of, 28644
    • Research Site
  • Goyang-si, Korea, Republic of, 10380
    • Research Site
  • Goyang-si, Korea, Republic of, 10444
    • Research Site
  • Gwangju, Korea, Republic of, 61469
    • Research Site
  • Hwaseong-si, Korea, Republic of, 18450
    • Research Site
  • Incheon, Korea, Republic of, 403-720
    • Research Site
  • Incheon, Korea, Republic of, 405-760
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Research Site
  • Seoul, Korea, Republic of, 03312
    • Research Site
  • Seoul, Korea, Republic of, 08308
    • Research Site
  • Seoul, Korea, Republic of, 07061
    • Research Site
  • Suwon-si, Korea, Republic of
    • Research Site
  • Uijeongbu-si, Korea, Republic of, 11765
    • Research Site
  • Wonju-si, Korea, Republic of, 26426
    • Research Site
• Russian Federation
  • Ekaterinburg, Russian Federation, 620039
    • Research Site
  • Krasnoyarsk, Russian Federation, 660062
    • Research Site
  • Moscow, Russian Federation, 123423
    • Research Site
  • Saint Petersburg, Russian Federation, 196601
    • Research Site
  • Saint-Petersburg, Russian Federation, 194354
    • Research Site
  • Yaroslavl, Russian Federation, 150062
    • Research Site
• Taiwan
  • Hualien City, Taiwan, 970
    • Research Site
  • New Taipei, Taiwan, 231
    • Research Site
  • Taichung, Taiwan, 40705
    • Research Site
  • Taichung, Taiwan, 402
    • Research Site
  • Taipei, Taiwan
    • Research Site
  • Taipei, Taiwan, ROC 100
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures
• Female and male patients aged ≥18 and ≤ 90 years
• Two consecutive i-STAT potassium values, measured 60-minutes (± 10 minutes) apart, both ≥ 5.1 mmol/l and measured within 1 day of the first ZS dose on 48-hour open-label initial phase 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 for the duration of the study and for 3 months after the last dose of ZS/matching placebo to prevent pregnancy.

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study
• Participation in another clinical study with an investigational product during the last 3 months
• Pseudohyperkalemia signs and symptoms
• Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug
• Patients treated with resins,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 subjects' tasks associated with the protocol
• Female patients who are pregnant, lactating, or planning to become pregnant
• Patients with 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
• Patients with cardiac arrhythmias that require immediate treatment
• Patients on dialysis
• Patients who are blood donors should not donate blood during the study and for 3 months following their last dose of ZS

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sodium Zirconium Cyclosilicate (ZS) 5g; Suspension administered 5g orally once daily for 28 days after the first 48-hour open label initial phase.	Drug: Sodium Zirconium Cyclosilicate (ZS) 5g; Suspension administered 5g orally once daily for 28 days after the first 48-hour open label initial phase.
EXPERIMENTAL: Sodium Zirconium Cyclosilicate (ZS) 10g; Suspension administered 10g orally once daily for 28 days after the first 48-hour open label initial phase.	Drug: Sodium Zirconium Cyclosilicate (ZS) 10g; Suspension administered 10g orally three times per day, in the first 48-hour of the study for all patients (48-hour open label initial phase); Drug: Sodium Zirconium Cyclosilicate (ZS) 10g; Suspension administered 10g orally once daily for 28 days after the first 48-hour open label initial phase.
PLACEBO_COMPARATOR: Placebo; Suspension administered orally placebo once daily for 28 days after the first 48-hour open label initial phase.	Drug: Placebo; Suspension administered orally placebo once daily for 28 days after the first 48-hour open label initial phase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Least Square Mean S-K Level on Days 8-29	Comparison between placebo and the active ZS treatment groups (each dose group will be sequentially compared with placebo, starting with the highest and ending with the lowest dose) with regard to the mean S-K level during the 28-day randomized treatment study phase Days 8-29. The results in the table below are presented for RTP.	Through 28-day randomized treatment study phase day 8-29.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Achieving Normokalemia	Proportion of patients who achieve normokalemia during the initial phase at 24 and 48 hours. The results in the table below are presented for OLP. (h=hours).	Through 48-hour initial phase.
Exponential Rate of Change in S-K Levels	Exponential rate of change in S-K levels (blood) during the 48-hour open-label initial phase. The results in the table below are presented for OLP.	Through 48-hour initial phase.
Absolute Change From Baseline in S-K Levels	Absolute change from baseline in S-K levels at all measured time intervals. The results in the table below are presented for OLP.	Through 48-hour initial phase.
Percentage Change From Baseline in S-K Levels	Percentage change from baseline in S-K levels at all measured time intervals. The results in the table below are presented for OLP.	Through 48-hour initial phase.
Proportion of Patients Remaining Normokalemic	The proportion of patients who remain normokalemic (as defined by S-K between 3.5-5.0 mmol/l, inclusive) at the end of the 28-day randomized treatment study phase and during the 28-day randomized treatment study phase. The results in the table below are presented for RTP.	Through 28-day randomized treatment study phase day 8-29.
Proportion of Normokalemic Patients at Day 1 Through Day 29/Exit	The proportion of patients who are normokalemic (as defined by S-K between 3.5-5.0 mmol/l, inclusive) at Day 1 through Day 29/Exit in randomization phase. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Days Patients Remain Normokalemic	The number of days patients remain normokalemic during the 28-day randomized treatment study phase. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Mean Change in S-K Levels	The mean change in S-K levels evaluated relative to both baselines. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Mean Percentage Change in S-K Levels	The mean percentage change in S-K levels evaluated relative to both baselines. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Number of Hyperkalemic Patients	The results represent number of hyperkalemic patients during the 28-day randomized treatment study phase. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Mean Changes in S-Aldosterone and P Renin Levels	The mean changes from OLP baseline in S-Aldosterone and P-Renin levels. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Patient Reported Health State (EQ-5D) Questionnaire	Evaluate health state of patients using EQ-5D questionnaire. This scale is numbered from 0 to 100. 0 means the worst health you can imagine. 100 means the best health you can imagine. The results in the table below are presented for RTP.	Through study completion, an average of 37 days.

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 3, 2017
• Primary Completion (ACTUAL): February 14, 2018
• Study Completion (ACTUAL): February 14, 2018

Study Registration Dates

• First Submitted: July 22, 2016
• First Submitted That Met QC Criteria: August 18, 2016
• First Posted (ESTIMATE): August 23, 2016

Study Record Updates

• Last Update Posted (ACTUAL): August 19, 2020
• Last Update Submitted That Met QC Criteria: August 6, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia
• Other Study ID Numbers: D9480C00002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No