Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05271266 |
| Other study ID # |
D9483R00001 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 22, 2022 |
| Est. completion date |
December 6, 2023 |
Study information
| Verified date |
June 2024 |
| Source |
AstraZeneca |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The study is a multi-center prospective (primary data) non-interventional cohort study which
enrolls 1500 patients including new and ongoing users on SZC at Study Enrollment Day in
real-world clinical practice. The eligible study patients will be identified by physicians in
each study site by assessing the patients or reviewing the medical record.
The prescription (including initiation, dose-adjusting or interruption) or discontinuation of
SZC will be determined by physicians as per real-world clinical practice and in accordance
with the local label. Any AZ employee, or member of the research operation team must not
intervene in the decision-making of any physician or patient through any approach, at any
time during the study.
Every patient will be followed up according to standard clinical practice for 6 months from
enrolment.
Description:
Background/Rationale:
Hyperkalaemia (HK) is a common electrolyte disturbance in clinical practice, defined as serum
potassium (sK) beyond the normal range. The cut-off value for HK diagnosis is 5.0 mmol/L in
most international guidelines[1, 2]. HK changes potassium ion gradient across the cell
membrane and affects the excitability and conductivity of cardiomyocytes, leading to various
types of arrhythmias, including ventricular arrhythmia, cardiac arrest and sudden death[3].
In the general population, the prevalence of HK is about 2-3%[4-6]. In an epidemiological
survey among outpatients in China, 3.86% of general outpatients experienced HK, and the
proportion of patients who experienced HK increased in patients with chronic kidney disease
(CKD), heart failure, diabetes and hypertension [7].
Sodium Zirconium Cyclosilicate (SZC) is a non-absorbed, non-polymer inorganic powder with a
uniform micropore structure that preferentially captures potassium in exchange for hydrogen
and sodium cations. SZC captures potassium throughout the entire gastrointestinal (GI) tract
and reduces the concentration of free potassium in the GI lumen, thereby lowering sK levels
and increasing faecal potassium excretion to resolve HK[8].
The potassium-lowering effects of SZC have been demonstrated in three randomised,
double-blind, placebo-controlled trials in patients with HK [9-11]. In addition, two
open-label maintenance studies tested long-term safety of SZC[12, 13]. These five studies
included 1,760 patients given doses of SZC; 507 exposed for at least 360 days. In the
studies, SZC reduced sK and maintained normal sK levels regardless of the underlying cause of
HK, age, sex, race, comorbid disease or concomitant use of renin-angiotensin and aldosterone
system inhibitors (RAASi).
As of 21 September 2019, the data cut-off date, approximately 2,580 patients have been
cumulatively exposed to SZC in completed and on-going clinical trials. Based on the data
available now, oedema-related events (including fluid overload, fluid retention, generalised
oedema, hypervolaemia, localised oedema, oedema, oedema peripheral, peripheral swelling) and
hypokalemia are common (frequency ≥1/100 to >1/10) adverse reactions reported with SZC.
In December 2019, SZC was approved in China. It is indicated for the treatment of HK in
adults. According to the National Medical Products Administration (NMPA) Regulations, the
safety profile of a newly approved drug should be intensively monitored within 5 years from
the date of first approval for import. As compared with the pre-market phase II/III studies,
post-market real world observational studies can observe the product safety profile in a
broader population and reflect the situation in routine clinical practice, which can meet the
request of the Guidelines of Drug Intensive Monitoring of Manufacturers. This study is
expected to enhance and supplement currently available SZC safety and tolerability data with
expansion to broader Chinese population.
Objectives:
Primary objectives: To describe the safety and tolerability of SZC for hyperkalemia
management in Chinese patients in terms of adverse events (AEs), serious adverse events
(SAEs) and discontinuations of SZC due to adverse events (DAEs), and specific AEs (oedema and
hypokalemia).
Secondary objectives:
- To describe the safety and tolerability of SZC for HK management in Chinese
hyperkalaemic patients in terms of AEs, SAEs and DAEs, and specific AEs (oedema and
hypokalemia) judged by the study investigators to be causally related to SZC.
- To understand the treatment pattern of SZC in real-world clinical practice for treating
HK in Chinese patients.
- To describe the sK level of patients treated with SZC during the observational period
Methods:
Study design: The study is a multi-center prospective observational cohort study which will
enroll patients who are ongoing and new users for HK management on SZC at study enrolment in
real-world clinical practice. The eligible patients will be identified by physicians in each
study site by assessing the patients or reviewing the medical record.
The prescription (including initiation, dose-adjusting or interruption) or discontinuation of
SZC will be determined by physicians as per real-world clinical practice and in accordance
with the local label. Any AZ employee, or member of the research operation team will not
intervene the decision-making of any physician or patient through any approach, at any time
during the study.
Every patient will be followed up according to standard clinical practice for 6 months from
enrolment.
At Study Enrollment Day (Day 1) the patients will be classified into 2 groups as new user
group and ongoing user group. New users are defined that the patients without SZC treatment
within 7 days before enrollment take SZC on Study Enrollment Day. Ongoing users are defined
that the patients with SZC treatment within 7 days before Study Enrollment Day continue SZC
treatment after enrollment. The patients with previous SZC treatment who will not continue
taking SZC treatment after enrollment will not be included.
Per standard clinical practice, new users of SZC should visit doctors within 1-3 days after
initiation of treatment for potassium re-testing, while ongoing users should visit doctors
once every 1-2 month for potassium monitoring or chronic disease consultation.
For new user group
- The "study index SZC treatment episode" starts at Study Enrollment Day.
- Follow-up visits will be planned on the 3rd day, the 1st month, the 3rd month and the
6th month from Study Enrollment Day.
For ongoing user group
- The "study index SZC treatment episode" started prior Study Enrollment Day.
- Follow-up visits will be planned on the 1st month, the 3rd month and the 6th month from
Study Enrollment Day.
Visits of Day 1 (Study Enrolment Day) and Day 3 (only applicable for patients in new user
group) are onsite. For visits at Month 1, Month 3 and Month 6, if the patient continues
taking SZC treatment at the visit time points, his/her visit will be onsite. Otherwise, the
visit will be conducted by phone-call. At each visit, safety outcomes, sK measurements data
(if available), treatment data of SZC (as applicable) and other related data (if available)
will be collected, as detailed in Section 6.1.2.
Data Source: This study will be based on primary (prospective) data collected from
approximately 60 hospitals in China recruiting 1500 patients. The site investigators will be
responsible for ensuring that all the required data are collected and entered into the
electronic case report form (eCRF).
Study Population: This study will enroll Chinese patients who are new and ongoing users of
SZC defined above at Study Enrolment Day. Eligible patients can be those under or not
dialysis treatment.
Exposure: Drug exposure of SZC treatment. Treatment dose and duration of SZC is at the
discretion of the patient's treating physician.
Outcome (s): Study measures will be collected at Study Enrollment Day (Day 1) and at the
scheduled study visits.
Primary Endpoints:
Occurrence of AEs, SAEs and DAEs, specifically AEs (oedema and hypokalemia). Oedema is
defined as an AE with one of the following preferred terms (PTs): Includes Fluid overload,
Fluid retention, Generalised oedema, Hypervolaemia, Localised oedema, Oedema, Oedema
peripheral, Peripheral swelling. Hypokalemia is defined as an AE with laboratory potassium
value test below 3.5 mmol/L
Secondary Endpoints:
- Occurrence of AEs, SAEs and DAEs, specifically AEs (oedema and hypokalemia), judged by
the investigators to be causally related to SZC.
- Average SZC daily dosage, frequency of different SZC dosages, duration of SZC treatment,
dose changes and reasons for any dose changes.
- Change in sK tested between V1 and V3, as well as average (within patient) sK levels
during the study. An evaluation of whether or not a patient tends to be normokalemic.
Two criteria for normokalemia will be considered:
- sK between 3.5 to 5.0 mmol/L, inclusive
- sK between 3.5 to 5.5 mmol/L, inclusive. Sample Size Justification: The total
sample size for this study is 1500 according to the mandatory request by NMPA. It's
assumed that the size of new users group will be ranging from 500 to 1000, while
the rest would be ongoing users group. Primary outcome measures will be: 1)
Percentage of overall AEs, SAEs, DAEs and specific AEs (oedema and hypokalemia)
during the first period (the time span between the first and the second visits
after SZC is initiated, only include new users group); and 2) Incidence rates of
overall AEs, SAEs, DAEs and specific AEs (oedema and hypokalemia) during second
period (starting after the initial treatment period is over, include ongoing users
group and possibly a subset of new users group). Detailed definition of first and
second period will be provided in statistical analysis section.
For percentage of overall AEs, assuming the point estimate would be 10%, the assumed size of
500 to 1000 new users could provide the 95% confidence interval (CI) estimation from [7.4%,
12.6%] to [8.1%, 11.9%].
For incidence rates of overall AEs, assuming the point estimate would be 107.88 per 100
person-years, the assumed size of 500 to 1000 patients over 0.5 to 1.5 months could provide
the 95% confidence interval from [71.32, 163.12] to [91.13, 127.72].
Sample size estimation under other scenarios as well as detailed description of estimation
approach will be provided in section 5.4.
Statistical Analysis:
This study is primarily of descriptive character with no formal hypothesis testing for the
objectives. The analyses will, as a rule, consist of estimates (of probabilities, rates,
means, etc.), with the corresponding 95% CIs, as well as supportive descriptive statistics
such as mean, standard deviation (SD), median, minimum, maximum, and quartiles.
