Clinical trial NCT04217590: Reduce Incidence of Pre-Dialysis Hyperkalaemia With Sodium Zirconium Cyclosilicate in Chinese Subjects
Official title: A Phase 3b, Multicentre, Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Reduce Incidence of Pre-Dialysis Hyperkalaemia With Sodium Zirconium Cyclosilicate in Chinese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hyperkalemia
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-01-03
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of Sodium Zirconium Cyclosilicate (SZC), as well as the appropriateness of the dosing mechanism, in Chinese end-stage renal disease (ESRD) patients on chronic haemodialysis.

Detailed description: This is a randomized, double-blind, placebo-controlled study to determine the safety and efficacy of SZC in ESRD subjects with hyperkalaemia and on stable haemodialysis. This study consists of a screening period, an 8-week randomized treatment period, and a follow-up period. Approximately 134 stable haemodialysis subjects with persistent pre-dialysis hyperkalaemia will be enrolled in the study across research sites in China.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
2. Subject must be ≥ 18 years of age inclusive, at the time of signing the informed consent form.
3. Subjects must have haemodialysis access consisting of an arteriovenous fistula, AV graft, or tunnelled (permanent) catheter which is expected to remain in place for the entire duration of the study.
4. Receiving haemodialysis (or hemodiafiltration) 3 times a week for treatment of end-stage renal disease (ESRD) for at least 3 months before randomization.
5. Pre-dialysis S-K \> 5.4 mmol/L after long inter-dialytic interval and \> 5.0 mmol/L after at least one short inter-dialytic interval during screening (as assessed by central lab).
6. Prescribed dialysate K concentration ≤ 3 mmol/L during screening.
7. Sustained Qb ≥ 200 ml/min and spKt/V ≥ 1.2 (or URR ≥ 63) on stable haemodialysis / haemodiafltration prescription during screening with prescription (time, dialyzer, blood flow \[Qb\], dialysate flow rate \[Qd\] and bicarbonate concentration) expected to remain unchanged during study.
8. Subjects must be receiving dietary counselling appropriate for ESRD subjects treated with haemodialysis / haemodiafiltration as per local guidelines, which includes dietary potassium restriction.

Exclusion Criteria:

1. Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic / thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12 weeks prior to randomization.
2. Pseudohyperkalaemia secondary to haemolyzed blood specimen (this situation is not considered screening failure, sampling or full screening can be postponed to a later time as applicable).
3. Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization.
4. Presence of cardiac arrhythmias or conduction defects that require immediate treatment.
5. 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.
6. History of QT prolongation associated with other medications that required discontinuation of that medication; congenital long QT syndrome or QTc(f) \> 550 msec; uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication or with transient atrial fibrillation associated with dialysis or peridialytic period are permitted.
7. Subjects treated with sodium polystyrene sulfonate (e.g. SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS, Resonium calcium) or patiromer (Veltassa) within 7 days before screening or anticipated in requiring any of these agents during the study.
8. Participation in another clinical study with an investigational product administered in the last 1 month before screening.
9. Haemoglobin \< 9 g/dL on screening (as assessed on Visit 1).
10. Laboratory diagnosis of hypokalaemia (K \< 3.5 mmol/L), hypocalcemia (Ca \< 8.2 mg/d or albumin-corrected Ca \< 8.0 mg/dL if the latter is used in local practice), hypomagnesemia (Mg \< 1.7 mg/dL) or severe acidosis (serum bicarbonate 16 mEq/L or less) in the 4 weeks preceding randomization.
11. Severe leukocytosis (\> 20 × 109/L) or thrombocytosis (≥ 450 × 109/L) during screening.
12. Polycythaemia (Hb \> 14 g/dL) during screening.
13. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
14. Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.
15. Previous randomisation in the present study.
16. For women only - currently pregnant (confirmed with positive pregnancy test or uterine ultrasound if pregnancy test is questionable) or breast-feeding.
17. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence.
18. Lack of compliance with haemodialysis prescription (both number and duration of treatments) during the two-week period preceding screening (100% compliance required).
19. Subjects unable to take investigational product drug mix.
20. Scheduled date for living donor kidney transplant.
21. Subjects with a life expectancy of less than 6 months.
22. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
23. History of alcohol or drug abuse within 2 years prior to randomization.

Primary outcomes:
measure: Percentage of Responders
timeFrame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
Secondary outcomes:
measure: Maximum Pre-dialysis S-K Values After SIDI and LIDI Below or Equal to 5.5 mmol/L During Evaluation Period
timeFrame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
measure: Pre-dialysis S-K After LIDI Between 3.5 and 5.5 mmol/L During the Evaluation Period
timeFrame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
measure: Instances of Pre-dialysis S-K After LIDI Between 4.0 and 5.0 mmol/L During the Evaluation Period
timeFrame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
measure: Expected Number of Normokalaemic (S-K 4.0-5.0 mmol/L) Instances
timeFrame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
measure: Instances of Potassium Gradient of < 3.0 mmol/L After LIDI During the Evaluation Period
timeFrame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
Other outcomes:
Locations:
city: Baotou
country: China
facility: Research Site
city: Baotou
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Dongguan
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Hefei
country: China
facility: Research Site
city: Hohhot
country: China
facility: Research Site
city: Jinan
country: China
facility: Research Site
city: Lanzhou
country: China
facility: Research Site
city: Lanzhou
country: China
facility: Research Site
city: Nanchang
country: China
facility: Research Site
city: Nanjing
country: China
facility: Research Site
city: Ningbo
country: China
facility: Research Site
city: Ningbo
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shenzhen
country: China
facility: Research Site
city: Shenzhen
country: China
facility: Research Site
city: Tianjin
country: China
facility: Research Site
city: Urumqi
country: China
facility: Research Site
city: Wenzhou
country: China
facility: Research Site
city: Wenzhou
country: China
facility: Research Site
city: Yangzhou
country: China
facility: Research Site
city: Yinchuan
country: China
facility: Research Site
Study officials:
affiliation: Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, China.
name: Zhaohui Ni
role: PRINCIPAL_INVESTIGATOR
References:
citation: Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GF. Potassium binders for chronic hyperkalaemia in people with chronic kidney disease. Cochrane Database Syst Rev. 2020 Jun 26;6(6):CD013165. doi: 10.1002/14651858.CD013165.pub2.