Safety of Oral Resin for Treatment of Hyperkalemia in Chinese Patients With Renal Insufficiency
Condition: Hyperkalaemia
MeSH terms: Renal Insufficiency; Hyperkalemia
Study type: Observational

Summary: 
      It is a multicenter, prospective, non-interventional cohort study, in order to evaluate the
      safety of oral resin for treatment of hyperkalemia in Chinese patients with renal
      insufficiency.
    

Detailed 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 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]. Furthermore，62% hospitalized HK patients accompanied by acute
      kidney injury (AKI)[8].

      Treatment options for HK are well documented, and urgent therapy is indicated for rapid and
      substantial elevations in sK. However, for patients with modest elevations in sK without
      cardiac and neuromuscular manifestations, oral resin is in line with clinical practice, both
      calcium polystyrene sulphonate (CPS) and sodium polystyrene sulfonate (SPS), are applicable
      to HK caused by acute and chronic renal dysfunction.

      CPS/SPS entraps potassium in the distal colon in exchange for calcium/ sodium to potassium.
      CPS may have an advantage over SPS because it avoids sodium retention. However, few clinical
      studies have evaluated the safety and efficacy of CPS/SPS in the treatment of HK. This study
      is expected to enhance and supplement the currently available CPS/SPS safety and
      effectiveness data in Chinese population in real world practice.

      Objectives:

      Primary objectives: To describe the safety and tolerability of CPS/SPS for HK management in
      Chinese patients with renal insufficiency in terms of adverse events (AEs), serious adverse
      events (SAEs) and discontinuations of CPS/SPS due to adverse events (DAEs).

      Secondary objectives:

        -  To describe the safety and tolerability of CPS/SPS for HK management in Chinese
           hyperkalaemic patients with renal insufficiency in terms of AEs, SAEs and DAEs judged by
           the study investigators to be causally related to CPS/SPS.

        -  To understand the treatment pattern of CPS/SPS in real-world clinical practice for
           treating HK in Chinese patients with renal insufficiency.

        -  To describe the sK level of patients with renal insufficiency treated with CPS/SPS
           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 CPS/SPS 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
      CPS/SPS will be determined by physicians as per real-world clinical practice and in
      accordance with the local label. Any AstraZeneca (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 Enrolment 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 starting CPS/SPS but
      without CPS/SPS treatment within 7 days before Day 1. Ongoing users are defined that the
      patients with CPS/SPS treatment within 7 days before Day 1 and continue CPS/SPS treatment
      after enrolment. The patients with previous CPS/SPS treatment who will not continue taking
      CPS/SPS treatment after enrolment will not be included.

      Per standard clinical practice, new users of CPS/SPS should visit doctors within 1-3 days
      after initiation of treatment for potassium re-testing, then new users and ongoing users
      should visit doctors at Month 1, Month 3 and Month 6 for potassium monitoring or chronic
      disease consultation.

      For new user group

        -  The "study index CPS/SPS treatment episode" starts at Study Enrolment Day.

        -  Follow-up visits will be planned on the 3rd day, the 1st month, the 3rd month and the
           6th month from Study Enrolment Day.

      For ongoing user group

        -  The "study index CPS/SPS treatment episode" started prior Study Enrolment Day.

        -  Follow-up visits will be planned on the 1st month, the 3rd month and the 6th month from
           Study Enrolment 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 CPS/SPS treatment at the visit time points, the 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 CPS/SPS (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 30 hospitals in China recruiting around 1000 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 with renal insufficiency who are
      new users or ongoing users of CPS/SPS defined above at Study Enrolment Day. Eligible patients
      can be those with or without hemodialysis treatment.

      Exposure: Treatment dose and duration of CPS/SPS is at the discretion of the patient's
      treating physician.

      Outcome (s): Study measures will be collected at Day 1 and at the scheduled study visits.

      Primary Endpoints:

      • Occurrence of AEs, SAEs and DAEs during the study.

      Secondary Endpoints:

        -  Occurrence of AEs, SAEs and DAEs judged by the investigators to be causally related to
           CPS/SPS.

        -  Average CPS/SPS daily dosage, frequency of different CPS/SPS dosages, duration of
           CPS/SPS treatment, dose changes and reasons for any dose changes.

        -  Change in sK tested between V1 and V2 (patients in new user group), 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: Assuming the
                expected ratio of patients on SPS vs. CPS would be around 2:1, then with the total
                of 1,000 patients, the number of patients on SPS and CPS would be approximately 650
                and 350.

      Among 350 patients on CPS, new users and ongoing users are expected to be 150 and 200; While
      among 650 patients on SPS, new users and ongoing users are expected to be 300 and 350
      Assuming the AE rate for different types of AE would be ranging from 1% to 12.8% for CPS
      [9]and 10% to 46.7% for SPS[10], current sample size could provide regarding 95% confidence
      interval (CI) as [0.1%, 5.7%] to [8.2%, 17.4%] for CPS and [6.6%, 13.4%] to [41.2%, 51.9%]
      for SPS, estimated using Normal Approximation and Clopper-Pearson's exact method (for AE rate
      of 1% only), which meets with general clinical requirements.

      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        This study will enroll eligible Chinese patients who are new and ongoing users on CPS/SPS
        at Study Enrollment from approximately 30 sites in China recruiting 1000 patients. New
        users are defined that the patients without CPS/SPS treatment within 7 days before Study
        Enrollment Day takeCPS/SPS treatment on Study Enrollment Day. Ongoing users are defined
        that the patients with CPS/SPS treatment within 7 days before Study Enrollment Day continue
        CPS/SPS treatment after enrollment. The patients with previous CPS/SPS treatment who will
        not continue taking CPS/SPStreatment after enrollment will not be included. Eligible
        patients will be those who meet all inclusion criteria but not any exclusion criteria.
        Eligible patients can be patients with or without hemodialysis treatment.