Clinical trial NCT05535920: A Prospective, Randomized, Open-Label, Cross-Over Study of Lokelma to Control Interdialytic Hyperkalemia
Official title: A Prospective, Randomized, Multi-Center, Open-Label, Cross-Over Study of Lokelma to Control Interdialytic Hyperkalemia Following Augmentation of Dialysate Potassium
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hyperkalemia
Lead sponsor: NephroNet, Inc.
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2022-09-10
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Chronic outpatient hemodialysis patients have high rates of rapid changes in potassium and other electrolytes critical to the generation cardiac arrythmias. A growing body of data suggests that intra-dialytic K+ levels fall to level of 2.0 or lower and are a potential major contributor to the generation of atrial fibrillation, bradycardia, and other clinically significant arrhythmias. We propose that raising the dialysate bath to 3.0 K+ from current standard of care levels of 2.0 K+ will reduce levels of hypokalemia-induced arrhythmias. We further propose that the use of sodium zirconium cyclosilicate (Lokelma) will ensure that secondary hyperkalemia is controlled following the introduction of the 3.0 K+ dialysate bath.
Primary purpose: PREVENTION

Brief summary: A Prospective, RanDomized, Multi-Center, Open-Label, Cross-Over Study of Sodium Zirconium Cyclosilicate to Control Interdialytic HyperkalemiA Following Augmentation of Dialysate Potassium: Efficacy to Reduce the Incidence of Post-Dialysis Atrial Fibrillation and Clinically SignificanT Cardiac Arrhythmias - ADAPT Trial

Detailed description: This is a prospective, open-labelled, randomized, 2x2 cross-over design study of 88 patients with end stage renal disease (ESRD) receiving routine out-patient dialysis using a standard 2.0 potassium ion (K+)/2.5 calcium ion (Ca++) dialysate bath. The overall aim of the study is to determine whether converting stable hemodialysis patients from a "standard" 2.0 K+/2.5 Ca+ dialysate (without Lokelma) to a 3.0 K+/2.5 Ca++ mEq dialysate supplemented with the orally administered potassium binder sodium zirconium cyclosilicate (Lokelma) to treat interdialytic hyperkalemia will reduce the incidence and duration of post-dialysis atrial fibrillation.

Eligibility criteria: Inclusion Criteria:

* Provision of informed consent prior to any study-specific procedures
* Female or male aged above 18 years
* Patients with ESRD receiving hemodialysis three times per week for a minimum of 3 months
* Patients must have two (2) pre-dialysis K+ measurements between 5.1 and 6.5 mEq/L by Piccolo POCT following the long dialytic "weekends" (i.e., on two consecutive Mondays for patients on a Monday-Wednesday-Friday dialysis schedule or on two consecutive Tuesdays for patients on a Tuesday-Thursday-Saturday dialysis schedule) during screening, before insertion of the cardiac loop recorder.
* Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) They should have been stable on their chosen method of birth control for a minimum of 1 month before entering the study and willing to remain on the birth control until 4 weeks after the last dose.

Exclusion Criteria:

-

Exclusion Criteria Related to the Underlying Condition:

* Patients with a QTc(f) \> 550 msec and/or Congenital long QT syndrome
* Patients with a Haemoglobin \< 9 g/dl.
* Patients with any medical condition, including active, clinically significant infection or liver disease, that in the opinion of the investigator or Sponsor may pose a safety risk to a subject in this study, which may confound safety or efficacy assessment and jeopardize the quality of the data, or may interfere with study participation.
* Patient receiving peritoneal or home hemodialysis
* Patient receiving hemodialysis via a tunneled inferior vena cava (IVC) catheter and known central stenosis of access extremity
* Patient receiving outpatient hemodialysis for \< 3 months
* Patient receiving outpatient hemodialysis for prolonged Acute Kidney Injury (AKI) and considered by the site Principal Investigator (PI) likely to achieve renal recovery within 6 months Note: Patients receiving out-patient hemodialysis for AKI for longer than 6 months with no demonstrable renal clearance can be screened for study participation.
* Patient currently receiving a 1.0 K+, 3.0 K+ dialysate bath and unwilling to convert to a 2.0 K+/2.5 Ca++ dialysate bath
* Subject unwilling to convert from a 2.0 K+ dialysate bath to a 3.0 K+ dialysate bath
* Two or more pre-dialysis K+ of \< 5.1 or \> 6.5 mEq/L measured by Piccolo POCT after the long dialytic "weekends" during screening Note: If one of the two screening pre-dialysis K+ levels is between 4.6 to 5.0 mEq/L or 6.6 to 7.0 mEq/L, the patient can undergo an additional whole blood Piccolo POCT K+ measurement. Patients who fail the third whole blood Piccolo POCT K+ measurement will be considered ineligible for study participation. Note: Screen failures can be re-screened once to confirm eligibility in the study.
* Any documented whole blood Piccolo POCT K+ measurement that falls below 4.6 mEq/L or exceeds 7.0 mEq/l during the screening period
* Current use of a medication for treatment of hyperkalemia (e.g., Patiromer).
* Note: If a medication for treatment of hyperkalemia is stopped prior to or after the consenting process, the subject will undergo a one week washout prior to the first whole blood Piccolo POCT K+ measurement. Exclusion Criteria Related to Other Medical Conditions and Treatments:
* Anticipated life expectancy of 3 months duration
* Development of atrial fibrillation requiring hospitalization, medical therapy, anticoagulation, or cardioversion during study pre-screening or screening period
* Patient with a known placement of a dual or single chamber pacemaker
* Patient with an automatic implantable cardiac defibrillator (AICD)
* Patient with a LINQ implanted cardiac loop recorder with less than 6 months of battery life.
* Current use of amiodarone or other anti-arrhythmic therapy. Note: Patients on such medications must undergo a two week washout prior to the first whole blood Piccolo POCT K+ measurement.
* Known history of cardiac arrhythmias due to prolonged QT syndrome
* Subject unwilling to receive an implanted LINQ cardiac loop recorder (unless 6 months are remaining in their previously implanted device).
* Known active drug abuse
* Positive hepatitis C polymerase chain reaction (PCR) test with active viral deoxyribonucleic acid (DNA) shedding or chronic active hepatitis B as evidenced by detectable surface antigen from standard of care routine dialysis labs. Note: Patients with negative PCR DNA testing for either hepatitis B or C will be allowed to participate in the study.
* Known to have tested positive for human immunodeficiency virus (HIV) from standard of care routine dialysis labs.
* For women only: currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
* Patients with known and/or active severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders or diabetic gastroparesis Exclusion Criteria Related to the Investigational Product (IP):
* Known hypersensitivity to sodium zirconium cyclosilicate (Lokelmaâ).

Other/General Exclusion Criteria:

* Previous randomization in the present study. Note: Screen failures can be re-screened once to confirm eligibility in the study.
* Participation in another interventional (non-observational) clinical study within 4 weeks prior to enrollment in the present study

Primary outcomes:
measure: The change in atrial Fibrillation events
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
Secondary outcomes:
measure: Frequency and duration of CSCAs (bradycardia, ventricular tachycardia and/or asystole)
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
measure: Whether or not K+ outside of the 4.0 to 5.5 mEq/L safety range (Yes/No binary outcome measure).
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
Other outcomes:
measure: Total number of hypokalemic events defined as Piccolo POCT or laboratory-measured K+ of < 3.5 mEq/L.
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
measure: Number of events (measured promptly prior to the termination of dialysis) where a Piccolo POCT measurement of K+ is < 3.5 mEq/L OR Ca++ is < 7.0 mEq/L, OR Mg++ is < 2.0 mg/dl, OR a PO4 level is <3.0 mEq/L
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
measure: Frequencies of AEs, SAEs, and withdrawals due to AEs, with focus on treatment-related events.
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
measure: Correlation between PBUTs (IS, PCS, and ADMA) and the frequency of atrial fibrillation events.
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
measure: Correlation between electrolyte levels and clinical events (intradialytic hypotension, muscle cramping, and cardiac events). Correlation between electrolytes falling below threshold levels
timeFrame: 8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods
Locations:
city: La Jolla
country: United States
facility: Balboa Research
state: California
city: Lawrenceville
country: United States
facility: Georgia Nephrology DBA Georgia Nephrology Research Institute
state: Georgia
city: Fort Wayne
country: United States
facility: Nephrology Associates of Northern Illinois and Indiana (NANI)
state: Indiana
city: Kansas City
country: United States
facility: Clinical Research Consultants
state: Missouri
city: Asheville
country: United States
facility: Mountain Kidney & Hypertension Associates
state: North Carolina
Study officials:
affiliation: NephroNet, Inc.
name: James Tumlin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NephroNet, Inc.
name: Jeremy Whitson, BS
role: STUDY_DIRECTOR
References: