A Study to Evaluate a Potassium Normalization Treatment Regimen Including Sodium Zirconium Cyclosilicate (ZS) Among Patients With S-K ≥5.8 (ENERGIZE)

A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate a Potassium Normalization Treatment Regimen Including Sodium Zirconium Cyclosilicate (ENERGIZE)

The study is designed to determine if ZS 10g administered up to three times over 10h added to insulin and glucose in patients presenting with hyperkalemia will prove tolerable and efficacious. Patients will receive ZS or Placebo on top of standard of care treatment with insulin and glucose.

Study Overview

• Status: Completed
• Conditions: Hyperkalemia
• Intervention / Treatment: Drug: Sodium Zirconium Cyclosilicate(ZS); Drug: Insulin; Drug: Glucose; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Esbjerg, Denmark, 6700
    • Research Site
  • Herning, Denmark, 7400
    • Research Site
• Italy
  • Novara, Italy, 28100
    • Research Site
  • Piombino, Italy, 57025
    • Research Site
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • Research Site
  • Kemerovo, Russian Federation, 650002
    • Research Site
  • Moscow, Russian Federation, 121374
    • Research Site
  • Moscow, Russian Federation, 115516
    • Research Site
  • Perm, Russian Federation, 614990
    • Research Site
  • Ryazan, Russian Federation, 390039
    • Research Site
  • Saint-Petersburg, Russian Federation, 198205
    • Research Site
  • Yaroslavl, Russian Federation, 150062
    • Research Site
  • Yekaterinburg, Russian Federation, 620039
    • Research Site
• United States
  • Alabama
    • Montgomery, Alabama, United States, 36106
      • Research Site
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Research Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Research Site
    • Detroit, Michigan, United States, 48201
      • Research Site
    • Detroit, Michigan, United States, 48235
      • Research Site
    • Royal Oak, Michigan, United States, 48073
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • New York
    • Stony Brook, New York, United States, 11794
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Research Site
    • Winston-Salem, North Carolina, United States, 27157
      • Research Site
  • Texas
    • El Paso, Texas, United States, 79905
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 128 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

≥ 18 years of age

Potassium ≥5.8 mmol/L

Exclusion Criteria:

Possible pseudohyperkalaemia

Hyperkalaemia caused by any condition for which a therapy directed against the underlying cause of hyperkalaemia would be a better treatment option than treatment with insulin and glucose.

Dialysis session expected within 4h after randomization

Treated with any therapy intended to lower S-K between arriving at the hospital and randomization during Visit 1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZS+insulin+glucose; ZS will be administered in addition to insulin and glucose. Insulin and glucose is the current standard of care to treat serum potassium ≥5.8mmol/L.	Drug: Sodium Zirconium Cyclosilicate(ZS); Suspension administered orally for a treatment period of 24h. Single dose contains 2 sachets of ZS 5g. 10g administered up to three times over 10h (at 0, 4 and 10h).; Other Names: ZS, ZS-9; Drug: Insulin; Insulin 0.1 units/kg administered as a bolus or for up to 30 minutes.; Drug: Glucose; Glucose 25g administered IV <15 minutes before the insulin.
Placebo Comparator: Placebo+insulin+glucose; Placebo will be administered in addition to insulin and glucose. Insulin and glucose is the current standard of care to treat serum potassium ≥5.8mmol/L.	Drug: Insulin; Insulin 0.1 units/kg administered as a bolus or for up to 30 minutes.; Drug: Glucose; Glucose 25g administered IV <15 minutes before the insulin.; Drug: Placebo; Suspension administered orally for a treatment period of 24h. 2 sachets administered up to three times over 10h (at 0, 4 and 10h).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Absolute Change in S-K From Baseline Until 4h After Start of Dosing With SZC/Placebo	The least squares means (LS-means) are derived from a linear regression model of absolute change in S-K at 4h with the following covariates: treatment group; baseline S-K; time from the start of dosing insulin to the start of dosing SZC/placebo and the dose (units/kg) of the first course of insulin. The 95% CI is associated with LS-Means.	Baseline to 4h potassium measurements.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fraction of Patients Responding to Therapy Defined as: S-K <6.0mmol/L Between 1 and 4h and S-K <5.0mmol/L at 4h; and no Additional Potassium Lowering Therapy From 0 to 4h With Exception of the Initial Insulin Treatment	Additional therapies for hyperkalaemia are 2nd dose of insulin, Beta-agonists, Diuretics, Dialysis, Sodium bicarbonate and Potassium binders when administered with the expressed intent to lower S-K. Patients with any missing potassium value from 1h to 4h inclusive will be treated as non-responders.	Baseline to 4h potassium meansurements.
The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo	Proportion of patients achieving normokalaemia, S-K 3.5-5.0 mmol/L, at 1, 2 and 4h after start of dosing	Baseline to 4h potassium meansurements.
The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo		Baseline to 4h potassium meansurements.
The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo		Baseline to 4h potassium meansurements.
The Fraction of Patients Administered Additional Potassium Lowering Therapy Due to Hyperkalaemia From 0 to 4h.	Additional therapies for hyperkalaemia are 2nd dose of insulin, Beta-agonists, Diuretics, Dialysis, Sodium bicarbonate and Potassium binders when administered with the expressed intent to lower S-K.	Baseline to 4h potassium meansurements.
Mean Absolute Change in S-K From Baseline to 1h and 2h After Start of Dosing With SZC/Placebo	The least squares means (LS-means) are derived from a linear regression model of absolute change in S-K at 1h and 2h with the following covariates: treatment group; baseline S-K; time from the start of dosing insulin to the start of dosing SZC/placebo and the dose (units/kg) of the first course of insulin. The 95% CI is associated with LS-Means.	Baseline to 2h potassium measurements.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Frank Peacock, MD, Baylor College of Medicine

Publications and helpful links

General Publications

• Peacock WF, Rafique Z, Vishnevskiy K, Michelson E, Vishneva E, Zvereva T, Nahra R, Li D, Miller J. Emergency Potassium Normalization Treatment Including Sodium Zirconium Cyclosilicate: A Phase II, Randomized, Double-blind, Placebo-controlled Study (ENERGIZE). Acad Emerg Med. 2020 Jun;27(6):475-486. doi: 10.1111/acem.13954. Epub 2020 Mar 28.

Helpful Links

• CSP_redacted_version
• SAP_redacted_version

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2018
• Primary Completion (Actual): December 21, 2018
• Study Completion (Actual): December 21, 2018

Study Registration Dates

• First Submitted: October 23, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 9, 2017

Study Record Updates

• Last Update Posted (Actual): January 28, 2020
• Last Update Submitted That Met QC Criteria: January 17, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: D9480C00005; 2017-003955-50 (EudraCT Number)

Drug and device information, study documents

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