Heart Failure With Reduced Ejection Fraction, Hyperkalaemia
Conditions
Brief summary
The main objective of this study is to evaluate the efficacy of SZC as compared with placebo in keeping potassium levels within the normal range (3.5-5.0 mEq/L) while on spironolactone ≥25 mg daily without assistance of rescue therapy for hyperkalaemia (HK).
Detailed description
REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study that includes the following 3 phases: screening, 4-6 week open-label run-in phase where sodium zirconium cyclosilicate (SZC) and spironolactone will be optimized, followed by a 6-month double-blind, placebo-controlled, randomized withdrawal treatment phase. Patients meeting the following criteria will enter the 4-6 week open-label run-in phase: symptomatic heart failure with reduced ejection fraction (HFrEF); receiving an angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), or angiotensin receptor-Neprilysin inhibitor (ARNi); receiving no spironolactone or eplerenone, or receiving low-dose spironolactone (\<25 mg daily); receiving a beta-blocker unless contraindicated; AND with hyperkalemia (sK+ 5.1-5.9 mEq/L) and an eGFR \>/= 30 mL/min/1.73m2, OR normokalemic (sK+ 3.5-5.0 mEq/L) and 'at risk' of developing hyperkalemia (ie, history of hyperkalemia within the past 36 months and eGFR \>/= 30 mL/min/1.73m2, or sK+ 4.5-5.0 mEq/L and eGFR 30-60 mL/min/1.73m2 and/or age \>75 years). Patients who are normokalemic on SZC and receiving spironolactone \>/= 25 mg daily at the end of the open-label run-in phase will enter the 6-month double-blind, placebo-controlled, randomized withdrawal treatment phase. Eligible patients will be randomized 1:1, stratified by run-in phase sK+ cohort.
Interventions
Investigational medicinal product
DRUGPlacebo
Placebo comparator
OTHERSpironolactone
Background intervention. During the run-in phase, spironolactone will be initiated/uptitrated up to a maximum of 50 mg per day. During the randomized withdrawal phase the spironolactone dose at the end of the run-in phase will be maintained.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
All participants entering the double-blind, randomised treatment period will be centrally assigned to randomised study intervention using an Interactive Response Technology/Randomisation and Trial Supply Management (IRT/RTSM). Randomisation will be stratified by the sK+ cohort determined by central laboratory at the start of the open-label phase (Day 1). Before the study is initiated, the telephone number and call-in directions for the IRT and/or the log in information and directions for the RTSM will be provided to each site. The IRT/RTSM will provide to the investigator(s) or pharmacists the kit identification number to be allocated to the participant at the dispensing visit. Routines for this will be described in the IRT/RTSM user manual that will be provided to each centre. The randomisation code should not be broken except in medical emergencies when the appropriate management of the participant requires knowledge of the treatment randomisation.
Intervention model description
REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Adults aged ≥18 years * Potassium and estimated glomerular filtration rate (eGFR): * Cohort 1: sK+ 5.1-5.9 mEq/L at screening/study enrolment and eGFR ≥30 mL/min/1.73 m2; OR * Cohort 2: Normokalaemic (sK+ 3.5-5.0 mEq/L) at screening and 'at risk' of developing HK defined as any of the following: * Have a history of HK (sK+ \>5.0 mEq/L) within the prior 36 months and eGFR ≥30 mL/min/1.73 m2; or * sK+ 4.5-5.0 mEq/L and eGFR 30 to 60 mL/min/1.73 m2; or * sK+ 4.5-5.0 mEq/L, and age \>75 years * Symptomatic HFrEF (New York Heart Association \[NYHA\] class II-IV), which has been present for at least 3 months * Left ventricular ejection fraction (LVEF) ≤40% * Receiving angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), or angiotensin receptor-Neprilysin inhibitor (ARNi) * Not on or on low-dose spironolactone or eplerenone (\<25 mg daily) * Receiving beta-blocker unless contraindicated
Exclusion criteria
* Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, or severe stenotic valve disease as a primary cause of HF * Current inpatient hospitalisation with unstable HF, defined as any of the following: * Systolic blood pressure \<95 mmHg during the 6 hours prior to screening. * Intravenous diuretic therapy during the 12 hours prior to screening. * Use of intravenous inotropic drugs during the 24 hours prior to screening. * Received mechanical circulatory support during the 48 hours prior to screening * Previous cardiac transplantation or implantation of a ventricular assistance device (VAD) or similar device, or transplantation or implantation expected after randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Who Achieved Response, Defined as Serum Potassium (sK+) Within 3.5 to 5.0 mEq/L, Spironolactone Greater Than or Equal to 25 mg Daily, no Rescue Therapy for Hyperkalaemia | From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months | The median percentages of participants having a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The treatment effect was analysed using a generalised estimating equation (GEE) model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants Who Achieved Response, Defined as sK+ Within 3.5-5.0 mEq/L, on the Same Dose of Spironolactone as Randomisation, no Rescue Therapy for Hyperkalaemia | From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months | The median percentages of participants who achieved a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals. |
| Participants Who Achieved Response, Defined as Spironolactone Greater Than or Equal to 25 mg Daily | From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months | The median percentages of participants who achieved a response are presented. Response means that the requirement was met. Non-response was indicated for subjects lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals. |
| Time to First Instance of Decrease or Discontinuation of Spironolactone Dose Due to Hyperkalaemia | From randomisation to the EOT visit, up to 6 months | The time to first instance of decrease or discontinuation of spironolactone dose due to hyperkalaemia is presented in median time (days). The analysis was performed using a Cox regression model, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry). |
| Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT | At EOT visit (approximately 6 months post-randomisation) | The KCCQ is a 23-item instrument measuring, from the patients' perspectives, their heart failure-related symptoms, physical and social limitations, self-efficacy, and health-related quality of life (QoL) over the prior 2 weeks. It was scored as follows: Physical Limitation (items 1a-f), Symptom Stability (item 2), Symptom Frequency (items 3, 5, 7, and 9), Symptom Burden (items 4, 6, and 8), Self Efficacy (items 10 and 11), QoL (items 12, 13, and 14), and Social Limitation (items 15a-d). Scores were calculated by summing the responses within each domain and by taking the average. Scale scores were transformed to a 0 to 100 range, with 0 implying the lowest level of functioning and 100 for the highest level of functioning. The CSS was calculated as the average of Physical Limitation Score and Total Symptom Score (TSS) and the TSS was calculated as the average of Symptom Frequency and Symptom Burden Scores. The change from randomisation in KCCQ-CSS is reported. |
| Time to First Hyperkalaemia (sK+ Greater Than 5.0mEq/L) Episode | From randomisation to the end of treatment (EOT) visit, up to 6 months | The time to first hyperkalaemia episode for participants on SZC compared to placebo during the randomised-withdrawal period, with hyperkalaemia defined as sK+ greater than 5.0 mEq/L as assessed by central laboratory, is presented in median time (days). The analysis was performed using a Cox regression model including randomised treatment group and subject recruitment country, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry). Placebo group used as reference level in Cox model. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Location and Severity of Peripheral Oedema | During the randomised-withdrawal period and up to 14 days after discontinuation of SZC or placebo, up to 6.5 months | The location and severity of peripheral oedema that occurred during the randomised-withdrawal phase are presented. Participants with multiple peripheral oedema events were counted only once. The location of oedema is not mutually exclusive so multiple locations may apply for each participant. |
Countries
Brazil, Canada, Czechia, Hungary, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
This study consisted of two phases, an open-label run-in phase and a placebo-controlled randomized-withdrawal phase. Of the 366 participants enrolled in the open-label run-in phase, 203 participants entered into the randomized-withdrawal phase (102 received SZC treatment and 101 received placebo).
Participants by arm
| Arm | Count |
|---|---|
| Randomized-withdrawal Phase - SZC Group Participants continued on the SZC and spironolactone dose they were receiving at the end of the run-in phase. | 102 |
| Randomized-withdrawal Phase - Placebo Group Participants continued on the placebo and spironolactone dose they were receiving at the end of the run-in phase. | 101 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Run-in Phase | Adverse Event | 3 | 0 | 0 |
| Open-label Run-in Phase | Death | 3 | 0 | 0 |
| Open-label Run-in Phase | Failure to Meet Randomization Criteria | 144 | 0 | 0 |
| Open-label Run-in Phase | Lost to Follow-up | 1 | 0 | 0 |
| Open-label Run-in Phase | Study-specific Withdrawal Criteria | 2 | 0 | 0 |
| Open-label Run-in Phase | Withdrawal by Subject | 8 | 0 | 0 |
| Open-label Run-in Phase | Withdrawn from study due to withdrawal by co-investigator | 1 | 0 | 0 |
| Open-label Run-in Phase | Withdrawn from study due to withdrawal by PI | 1 | 0 | 0 |
| Randomised-withdrawal Phase | Adverse Event | 0 | 5 | 5 |
| Randomised-withdrawal Phase | Death | 0 | 1 | 2 |
| Randomised-withdrawal Phase | Development of Study-specific Withdrawal Criteria | 0 | 2 | 4 |
| Randomised-withdrawal Phase | Lost to Follow-up | 0 | 1 | 0 |
| Randomised-withdrawal Phase | Withdrawal by Subject | 0 | 2 | 2 |
| Randomised-withdrawal Phase | Withdrawn from study due to PD - Wrong doses of spironolactone | 0 | 1 | 0 |
| Randomised-withdrawal Phase | Withdrawn from study due to spironolactone was stopped on May 28, related hyperkalaemia | 0 | 1 | 0 |
| Randomised-withdrawal Phase | Withdrawn from study due to the participant did not have enough medication by issues in IWRS | 0 | 0 | 1 |
| Randomised-withdrawal Phase | Withdrawn from study due to the patient was random by mistake on this date he was an OLRIF | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Randomized-withdrawal Phase - SZC Group | Total | Randomized-withdrawal Phase - Placebo Group |
|---|---|---|---|
| Age, Continuous | 72.5 Years STANDARD_DEVIATION 7.88 | 70.9 Years STANDARD_DEVIATION 9.39 | 69.2 Years STANDARD_DEVIATION 10.46 |
| Age, Customized 18-64 years | 18 Participants | 50 Participants | 32 Participants |
| Age, Customized 65-84 years | 79 Participants | 142 Participants | 63 Participants |
| Age, Customized >=85 years | 5 Participants | 11 Participants | 6 Participants |
| Country BRA | 31 Participants | 50 Participants | 19 Participants |
| Country CAN | 7 Participants | 23 Participants | 16 Participants |
| Country CZE | 3 Participants | 16 Participants | 13 Participants |
| Country ESP | 33 Participants | 59 Participants | 26 Participants |
| Country GBR | 9 Participants | 13 Participants | 4 Participants |
| Country HUN | 5 Participants | 10 Participants | 5 Participants |
| Country POL | 8 Participants | 18 Participants | 10 Participants |
| Country USA | 6 Participants | 14 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 67 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 136 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 10 Participants | 5 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 8 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 91 Participants | 185 Participants | 94 Participants |
| Sex: Female, Male Female | 26 Participants | 52 Participants | 26 Participants |
| Sex: Female, Male Male | 76 Participants | 151 Participants | 75 Participants |
| Type 2 diabetes at baseline No | 75 Participants | 151 Participants | 76 Participants |
| Type 2 diabetes at baseline Yes | 27 Participants | 52 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 362 | 2 / 101 | 2 / 101 |
| other Total, other adverse events | 9 / 362 | 20 / 101 | 25 / 101 |
| serious Total, serious adverse events | 11 / 362 | 23 / 101 | 22 / 101 |
Outcome results
Primary
Participants Who Achieved Response, Defined as Serum Potassium (sK+) Within 3.5 to 5.0 mEq/L, Spironolactone Greater Than or Equal to 25 mg Daily, no Rescue Therapy for Hyperkalaemia
The median percentages of participants having a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The treatment effect was analysed using a generalised estimating equation (GEE) model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.
Time frame: From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized-withdrawal Phase - SZC Group | Participants Who Achieved Response, Defined as Serum Potassium (sK+) Within 3.5 to 5.0 mEq/L, Spironolactone Greater Than or Equal to 25 mg Daily, no Rescue Therapy for Hyperkalaemia | 72.1 Percentage of participants |
| Randomized-withdrawal Phase - Placebo Group | Participants Who Achieved Response, Defined as Serum Potassium (sK+) Within 3.5 to 5.0 mEq/L, Spironolactone Greater Than or Equal to 25 mg Daily, no Rescue Therapy for Hyperkalaemia | 35.7 Percentage of participants |
p-value: <0.00195% CI: [2.89, 6.86]GEE model
Secondary
Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT
The KCCQ is a 23-item instrument measuring, from the patients' perspectives, their heart failure-related symptoms, physical and social limitations, self-efficacy, and health-related quality of life (QoL) over the prior 2 weeks. It was scored as follows: Physical Limitation (items 1a-f), Symptom Stability (item 2), Symptom Frequency (items 3, 5, 7, and 9), Symptom Burden (items 4, 6, and 8), Self Efficacy (items 10 and 11), QoL (items 12, 13, and 14), and Social Limitation (items 15a-d). Scores were calculated by summing the responses within each domain and by taking the average. Scale scores were transformed to a 0 to 100 range, with 0 implying the lowest level of functioning and 100 for the highest level of functioning. The CSS was calculated as the average of Physical Limitation Score and Total Symptom Score (TSS) and the TSS was calculated as the average of Symptom Frequency and Symptom Burden Scores. The change from randomisation in KCCQ-CSS is reported.
Time frame: At EOT visit (approximately 6 months post-randomisation)
Population: Full Analysis Set: all participants with more than 50% of responses available at a visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized-withdrawal Phase - SZC Group | Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT | 71.27 Score on a scale | Standard Error 2.57 |
| Randomized-withdrawal Phase - Placebo Group | Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT | 72.27 Score on a scale | Standard Error 2.36 |
p-value: 0.72495% CI: [-6.64, 4.63]t-test, 2 sided
Secondary
Participants Who Achieved Response, Defined as sK+ Within 3.5-5.0 mEq/L, on the Same Dose of Spironolactone as Randomisation, no Rescue Therapy for Hyperkalaemia
The median percentages of participants who achieved a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.
Time frame: From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized-withdrawal Phase - SZC Group | Participants Who Achieved Response, Defined as sK+ Within 3.5-5.0 mEq/L, on the Same Dose of Spironolactone as Randomisation, no Rescue Therapy for Hyperkalaemia | 58.2 Percentage of participants |
| Randomized-withdrawal Phase - Placebo Group | Participants Who Achieved Response, Defined as sK+ Within 3.5-5.0 mEq/L, on the Same Dose of Spironolactone as Randomisation, no Rescue Therapy for Hyperkalaemia | 22.9 Percentage of participants |
p-value: <0.00195% CI: [2.78, 7.55]GEE model
Secondary
Participants Who Achieved Response, Defined as Spironolactone Greater Than or Equal to 25 mg Daily
The median percentages of participants who achieved a response are presented. Response means that the requirement was met. Non-response was indicated for subjects lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.
Time frame: From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized-withdrawal Phase - SZC Group | Participants Who Achieved Response, Defined as Spironolactone Greater Than or Equal to 25 mg Daily | 81.4 Percentage of participants |
| Randomized-withdrawal Phase - Placebo Group | Participants Who Achieved Response, Defined as Spironolactone Greater Than or Equal to 25 mg Daily | 49.5 Percentage of participants |
p-value: <0.00195% CI: [2.5, 7.52]GEE model
Secondary
Time to First Hyperkalaemia (sK+ Greater Than 5.0mEq/L) Episode
The time to first hyperkalaemia episode for participants on SZC compared to placebo during the randomised-withdrawal period, with hyperkalaemia defined as sK+ greater than 5.0 mEq/L as assessed by central laboratory, is presented in median time (days). The analysis was performed using a Cox regression model including randomised treatment group and subject recruitment country, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry). Placebo group used as reference level in Cox model.
Time frame: From randomisation to the end of treatment (EOT) visit, up to 6 months
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized-withdrawal Phase - SZC Group | Time to First Hyperkalaemia (sK+ Greater Than 5.0mEq/L) Episode | 65.0 Days |
| Randomized-withdrawal Phase - Placebo Group | Time to First Hyperkalaemia (sK+ Greater Than 5.0mEq/L) Episode | 9.0 Days |
p-value: <0.00195% CI: [0.37, 0.71]Regression, Cox
Secondary
Time to First Instance of Decrease or Discontinuation of Spironolactone Dose Due to Hyperkalaemia
The time to first instance of decrease or discontinuation of spironolactone dose due to hyperkalaemia is presented in median time (days). The analysis was performed using a Cox regression model, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry).
Time frame: From randomisation to the EOT visit, up to 6 months
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized-withdrawal Phase - SZC Group | Time to First Instance of Decrease or Discontinuation of Spironolactone Dose Due to Hyperkalaemia | NA Days |
| Randomized-withdrawal Phase - Placebo Group | Time to First Instance of Decrease or Discontinuation of Spironolactone Dose Due to Hyperkalaemia | NA Days |
p-value: 0.00695% CI: [0.17, 0.73]Regression, Cox
Other Pre-specified
Location and Severity of Peripheral Oedema
The location and severity of peripheral oedema that occurred during the randomised-withdrawal phase are presented. Participants with multiple peripheral oedema events were counted only once. The location of oedema is not mutually exclusive so multiple locations may apply for each participant.
Time frame: During the randomised-withdrawal period and up to 14 days after discontinuation of SZC or placebo, up to 6.5 months
Population: Safety Set Randomised
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: trace | 4 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: moderate | 7 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: mild | 1 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: mild | 5 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: moderate | 7 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: moderate | 8 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: moderate | 7 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: trace | 2 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: mild | 4 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: moderate | 5 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: trace | 4 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: trace | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: trace | 1 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: mild | 2 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: mild | 3 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Location of oedema: thigh oedema | 1 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: moderate | 7 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: mild | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Location of oedema: ankle oedema | 17 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: moderate | 1 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: trace | 4 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: trace | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: trace | 4 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: mild | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Location of oedema: pretibial oedema | 11 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: moderate | 1 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: mild | 5 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - SZC Group | Location and Severity of Peripheral Oedema | Location of oedema: pedal oedema | 13 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Location of oedema: pedal oedema | 10 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Location of oedema: pretibial oedema | 5 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: moderate | 1 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: moderate | 1 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: moderate | 1 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: trace | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Location of oedema: ankle oedema | 13 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Location of oedema: thigh oedema | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: trace | 3 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: mild | 5 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: trace | 5 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: mild | 4 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: moderate | 1 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pedal oedema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: trace | 4 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: mild | 6 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - right side: moderate | 1 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: trace | 6 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: mild | 6 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of ankle oedema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: trace | 1 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: mild | 2 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: moderate | 1 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: trace | 2 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: mild | 2 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of pretibial edema - left side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: mild | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: moderate | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - right side: severe | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: trace | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: mild | 0 Participants |
| Randomized-withdrawal Phase - Placebo Group | Location and Severity of Peripheral Oedema | Severity of thigh edema - left side: moderate | 0 Participants |