Clinical Trial Results:
A Phase II, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multicentre, Three Month Duration Potassium Reduction Initiative to Optimise RAAS Inhibition Therapy with Sodium Zirconium Cyclosilicate in Heart Failure (PRIORITIZE HF)
|
Summary
|
|
EudraCT number |
2018-000175-33 |
Trial protocol |
HU SK PL BG RO |
Global end of trial date |
22 May 2020
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
05 Jun 2021
|
First version publication date |
05 Jun 2021
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
D9484C00001
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03532009 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
AstraZeneca
|
||
Sponsor organisation address |
Södertälje, Södertälje, Sweden, SE-151 85
|
||
Public contact |
Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
|
||
Scientific contact |
Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
22 May 2020
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
22 May 2020
|
||
Was the trial ended prematurely? |
Yes
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The main objective of the study was to determine if there was a difference between sodium zirconium cyclosilicate (SZC) and placebo in renin-angiotensin aldosterone system (RAAS) blockade treatment.
|
||
Protection of trial subjects |
This study was conducted in accordance with the protocol and with the following:
- Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines;
- Applicable International Conference on Harmonisation Good Clinical Practice Guidelines;
- Applicable laws and regulations.
|
||
Background therapy |
Patients continued to receive their RAAS inhibition (RAASi) therapy as before randomisation, but additional monitoring of their local lab serum-potassium (S-K) allowed up-titration of their RAASi therapy to a target dose. | ||
Evidence for comparator |
Placebo was used as comparator in PRIORITIZE HF as the primary efficacy endpoints could have been affected by treating physicians knowing the treatment allocation of individual patients, and as there is no other drug currently approved or widely used to allow up-titration of RAASi in patients at high risk of hyperkalaemia. Hence placebo was a necessary and appropriate comparator. | ||
Actual start date of recruitment |
26 Jun 2018
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Brazil: 22
|
||
Country: Number of subjects enrolled |
Bulgaria: 16
|
||
Country: Number of subjects enrolled |
Canada: 8
|
||
Country: Number of subjects enrolled |
Hungary: 31
|
||
Country: Number of subjects enrolled |
Poland: 7
|
||
Country: Number of subjects enrolled |
Romania: 10
|
||
Country: Number of subjects enrolled |
Russian Federation: 63
|
||
Country: Number of subjects enrolled |
Slovakia: 16
|
||
Country: Number of subjects enrolled |
United States: 9
|
||
Worldwide total number of subjects |
182
|
||
EEA total number of subjects |
80
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
33
|
||
From 65 to 84 years |
134
|
||
85 years and over |
15
|
||
|
|||||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||||
Recruitment details |
This study was performed at 64 sites in 9 countries (Brazil, Bulgaria, Canada, Hungary, Poland, Romania, Russia, Slovakia, and the United States of America) between 26 June 2018 and 22 May 2020. | ||||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||||
Screening details |
Patients were randomised in a 1:1 ratio to receive SZC or placebo for 3 months while titrating RAASi therapies. The study was prematurely terminated due to the COVID-19 pandemic resulting in a reduced sample size (182 randomised patients as opposed to the planned 280 patients). | ||||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||
Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||
|
Arm title
|
Sodium zirconium cyclosilicate | ||||||||||||||||||||||||
Arm description |
Patients with S-K concentration > 5.0 millimole/litre (mmol/L) at the last assessment before randomisation received SZC 10 grams (g) orally 3 times daily (tid) for 2 days followed by SZC 5 g once daily (qd) for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Sodium zirconium cyclosilicate
|
||||||||||||||||||||||||
Investigational medicinal product code |
AZD7270
|
||||||||||||||||||||||||
Other name |
SZC
|
||||||||||||||||||||||||
Pharmaceutical forms |
Powder for oral suspension
|
||||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||||
Dosage and administration details |
Patients with S-K concentration > 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally 3 tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
|
||||||||||||||||||||||||
|
Arm title
|
Placebo | ||||||||||||||||||||||||
Arm description |
Patients with S-K concentration > 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||
Pharmaceutical forms |
Powder for oral suspension
|
||||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||||
Dosage and administration details |
Patients with S-K concentration > 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sodium zirconium cyclosilicate
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients with S-K concentration > 5.0 millimole/litre (mmol/L) at the last assessment before randomisation received SZC 10 grams (g) orally 3 times daily (tid) for 2 days followed by SZC 5 g once daily (qd) for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients with S-K concentration > 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Sodium zirconium cyclosilicate
|
||
Reporting group description |
Patients with S-K concentration > 5.0 millimole/litre (mmol/L) at the last assessment before randomisation received SZC 10 grams (g) orally 3 times daily (tid) for 2 days followed by SZC 5 g once daily (qd) for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Patients with S-K concentration > 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||
|
|||||||||||||||||||||||||
End point title |
Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3 | ||||||||||||||||||||||||
End point description |
RAASi treatment categories:
- No, or less than target dose, angiotensin converting enzyme inhibitors (ACEi)/ angiotensin receptor blockers (ARB)/ angiotensin receptor/ neprolysin inhibitors (ARNI) and no mineralocorticoid receptor antagonist (MRA);
- ACEi/ARB/ARNI at target dose and no MRA;
- MRA at less than target dose;
- MRA at target dose.
Missing values at 3 months were imputed using a multiple imputation approach with 10000 imputations. The imputation model included RAASi category at 3 months as the outcome variable and the following covariates: RAASi category, local lab-K, eGFR and systolic blood pressure measured at the last visit before the 3 months (starting with the randomisation visit) when all the covariates’ data were available.
All randomised patients with a non-missing value for the RAASi treatment category (after imputation) were included.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
At the end of the treatment visit (Month 3)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
SZC versus (vs) Placebo | ||||||||||||||||||||||||
Statistical analysis description |
The p-value was obtained by pooling the p-values from Chi-square tests performed on individual data sets using the F-distribution and reflects a global test of no difference in distribution of patients in the respective categories between SZC and placebo groups. The null hypothesis was that there is no difference between SZC and placebo in the distribution of percentage of patients in the 4 RAASi treatment categories. The hypothesis was tested at a significance level of 5%.
|
||||||||||||||||||||||||
Comparison groups |
Sodium zirconium cyclosilicate v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
176
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.426 | ||||||||||||||||||||||||
Method |
F-test | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Number of Patients who Experienced Adverse Events (AEs) During the Study | ||||||||||||||||||
End point description |
An AE is the development of any untoward medical occurrence in a patient or clinical study patient administered an investigational product (IP) and which does not necessarily have a causal relationship with the IP. An AE can be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of an IP.
A serious adverse event (SAE) is an AE occurring during any study phase, that fulfils one or more of the following criteria:
- Results in death;
- Is immediately life-threatening;
- Requires in-patient hospitalisation or prolongation of existing hospitalisation;
- Results in persistent or significant disability or incapacity;
- Is a congenital abnormality or birth defect;
- Is an important medical event that may jeopardise the patient or may require medical treatment to prevent one of the outcomes listed above.
The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
|
||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||
End point timeframe |
From Day 1 of treatment up to the end of the follow-up period (Week 17)
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Number of Patients who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters | ||||||||||||||||||||||||
End point description |
The number of patients who experienced clinically important abnormalities in clinical laboratory assessments as assessed by the Investigator are presented. Clinically important abnormalities in clinical laboratory parameters were reported as AEs. Clinical laboratory assessments included clinical chemistry, haematology and urinalysis performed at the central laboratory.
The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
|
||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||
End point timeframe |
From Day 1 of treatment up to the end of the follow-up period (Week 17)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Number of Patients who Experienced Clinically Important Abnormalities in Vital Signs Measurements | |||||||||||||||||||||
End point description |
The number of patients who experienced clinically important abnormalities in vital signs assessments as assessed by the Investigator are presented. Clinically important abnormalities in vital signs measurements were reported as AEs. Vital signs assessments included weight, pulse, and systolic and diastolic blood pressure measurements.
The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||
End point timeframe |
From Day 1 of treatment up to the end of the follow-up period (Week 17)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
||||||||||
End point title |
Number of Patients who Experienced Clinically Significant Changes in Electrocardiogram (ECG) Measurements | |||||||||
End point description |
The number of patients who experienced clinically significant changes in ECG measurements as assessed by the Investigator are presented. Clinically important abnormalities in ECG measurements were reported as AEs. 12-lead ECGs were obtained using a digital ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT (using QT interval corrected by Fredericia's algorithm) intervals.
The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
|
|||||||||
End point type |
Other pre-specified
|
|||||||||
End point timeframe |
From Day 1 of treatment up to the end of the follow-up period (Week 17)
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||||||||||||||
End point title |
Number of Patients who Experienced Low and High S-K Levels | |||||||||||||||||||||
End point description |
The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. Patients with S-K levels < 3.5 mmol/L were considered to have low S-K levels. Patients with S-K levels > 5.0 mmol/L were considered to have high S-K levels.
The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||
End point timeframe |
From Day 1 of treatment up to the end of the follow-up period (Week 17)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Number of Events of Low and High S-K Levels | |||||||||||||||||||||
End point description |
The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. Patients with S-K levels < 3.5 mmol/L were considered to have had an event of low S-K levels. Patients with S-K levels > 5.0 mmol/L were considered to have had an event of high S-K levels.
The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||
End point timeframe |
From Day 1 of treatment up to the end of the follow-up period (Week 17)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From Day 1 of treatment up to the end of the follow-up period (Week 17)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All non-serious adverse event results including totals include non-serious adverse events over the 5% frequency threshold only. The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients with S-K concentration > 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sodium zirconium cyclosilicate
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients with S-K concentration > 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||
Substantial protocol amendments (globally) |
|||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
20 Apr 2018 |
The amendment included:
- Updates to the Schedule of Activities.
- Wording added to clarify which S-K measurement was to be used to determine if patients have S-K > 5.0 mmol/L.
- A new section was added describing the process for study and site closure.
- A recommendation to perform the Visit 2 i-STAT assessment before other Visit 2 assessments (except Kansas City Cardiomyopathy Questionnaire) was added. |
||||||
27 Feb 2019 |
The amendment included:
- Updates to the Schedule of Activities.
- Updates to the objectives.
- Beta blocker language clarified.
- Added clarifications of RAASi titration.
- Updates to the inclusion and exclusion criteria.
- Modified wording to allow a patient to only be rescreened once.
- Wording for the requirement if a previous temporary discontinuation became permanent.
- Modified procedure for blood pressure measurements.
- Modified efficacy analyses to be based on the Full analysis set as opposed to the intent-to-treat principle using the Full analysis set.
- Added that missing data at 3 months will be imputed for the primary variable and changed the laboratory data shift tables to present baseline to the most extreme value during treatment.
- Method for multiplicity control was deleted. |
||||||
12 Jun 2019 |
The amendment included:
- The entire document was updated to use local laboratories for rapid ascertainment of S-K and creatinine for enrolment and randomisation purposes and for dose titration decisions rather than using the i-STAT device and to remove the requirement for an unblinded Investigator at the end of the study to manage patient RAASi treatment decisions.
- Updates to the laboratory assessments.
- New wording that patients treated with low dose of MRA at baseline, who did not have MRA increased specifically due to prior hyperkalaemia, were eligible for the study.
- New wording to define that up titration of study drug should be considered before down-titration RAASi if local lab-K > 5.0 and ≤ 6.0 mmol/L.
- Specified order of RAASi medication titration (first MRA, then ACEi/ARB/ARNI).
- Changed target dose of spironolactone from a range of 25-50 mg to 50 mg.
- Modified wording to clarify that patients should continue to complete all subsequent visits after study drug discontinuation. |
||||||
22 May 2020 |
The amendment (dated 26-May-2020) included:
- Updates to the eligibility criteria (patients with low dose baseline MRA could be enrolled into the study, and patients with lower baseline S-K were also eligible).
- An order shift in CSP RAASi up-titration guidance (to add/up-titrate MRA first, followed by ACEi/ARB/ARNI).
- General design updates. |
||||||
Interruptions (globally) |
|||||||
| Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| The study was prematurely terminated due to the COVID-19 pandemic resulting in a reduced sample size and a high premature treatment discontinuation rate. | |||||||
