CKD, Diabetes Mellitus, Type 2, Hyperkalemia
Conditions
Brief summary
The hypothesis is that 3 months' treatment with SZC versus placebo will enable RASi (Irbesartan) maximisation in a cohort of patients with diabetic kidney disease.
Detailed description
Inhibiting the renin angiotensin (RAS) system has been the cornerstone of therapy for patients with proteinuric CKD for almost 2 decades, to slow the decline in renal function, delay the presence of dialysis and reduce cardiovascular events and death. There is evidence in both the cardiac and renal literature that suggests that maximising the dose of RAS therapy leads to improved outcomes over smaller doses of RAS therapy. Indeed, many of the studies on which we base our care use doses which are higher than what the majority of our patients are taking. Thus patients are being systemically undertreated by therapies which have been shown to have robust reno protection. With up to 80% of patients on RASi therapy are not on maximal RASi therapy , putting them at risk of a more rapid progression and poorer outcomes and increased healthcare costs. An important reason for this is the presence or fear around hyperkalaemia. With reports of significantly increased rate of hyperkalaemia seen following increases in prescribing of RASi therapy. These concerns have lead NICE to recommend not starting patients on RASi therapy if their potassium is \>5mmol/l, and KDOQI guidelines recommending consideration of stopping RASi therapy if serum potassium is \>5.5mmol/l. ACE inhibitors and angiotensin receptor blockers are thought to confer long term renal protection through reduction of proteinuria. The reduction in glomerular pressure is a major mechanism leading to a reduction in proteinuria, and hence renal protection, however as a consequence there will also an acute fall in eGFR. Therefore, when starting/up titrating ACEi/ARB it is expected that there will be an acute fall in eGFR, which is expected to be more than compensated for due to the subsequent long term renal protection. Indeed, current NICE guidelines do not suggest any alteration in management until the drop in eGFR is \>25%. There is a currently huge unmet need to optimise RASi therapy in those patients with hyperkalaemia. There have been recent advances in novel therapeutics which can lower potassium in patients. One such agent is Sodium zirconium cyclosilicate (SZC). SZC is a highly selective inorganic cation exchanger designed to entrap potassium in the intestine. It has been shown to effective in lowering potassium in patients with heart failure, Diabetes, CKD and RASi therapy. With around a 1mmol/l fall in the serum potassium on those treated with SZC, compared to placebo. In the 5-large clinical trials it appears efficacious, well tolerated and safe.
Interventions
sachets of 5g or 10g given OD titrated to serum potassium
DRUGPlacebo
matched placebo given titrated according to potassium at a dose to 5 or 10g
Sponsors
Barts & The London NHS Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double blind randomised clinical trial.
Intervention model description
A Multi site, placebo controlled, double blind randomised clinical trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able and willing to provide written informed consent 2. Adults ≥ 18years old 3. Type 2 Diabetes 4. CKD defined as eGFR 25-60ml/min 5. Albuminuria with uACR measured at \>33.9.mg/mmol (300mg/g) 6. On a stable (\>4 weeks) of sub-maximal RASi dose, defined as any ACE or ARB dose up to and including 50% of maximum dose with evidence of hyperkalaemia potassium level \>5.0mmol/l OR not currently on RASi therapy due to documented issues of hyperkalaemia in the past necessitating RASi discontinuation
Exclusion criteria
1. Active malignancy 2. Patients who lack capacity to give informed consent 3. GI disturbance/chronic diarrhoea/stoma 4. Subjects with a life expectancy of less than 3 months. 5. Women who are pregnant, lactating, planning to become pregnant or unwilling to use effective methods of contraception during the study. 6. Presence of any condition which, in the opinion of the investigator, places the subject at undue risk or potentially jeopardizes the quality of the data to be generated including NYHA class III/IV. 7. History of acute eGFR fall with RASi therapy (\>30% in eGFR on initiation of RASi therapy) 8. Known hypersensitivity or previous anaphylaxis to SZC or Irbesartan 9. Hypotension: BP \<120/70mm/hg at screening despite no antihypertensive agent use 10. Uncontrolled Blood pressure: BP \>170/110 at screening 11. Evidence of prolonged QT on ECG QTc(f)\>550msec 12. History of QT prolongation associated with other medications that required discontinuation of that medication 13. Treatment with lithium, or dual blockade with ACEi and ARB or mineralocorticoid inhibitor 14. History of congenital long QT syndrome 15. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted 16. Current or recent (within 3 months) participation in a clinical trial involving an investigational medicinal product. 17. Current treatment with a potassium binder medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo | Study end (week 12) | Difference in proportion of patients on maximum dose (300mg) Irbesartan therapy at the end of 12 weeks compared to placebo. Proportion is calculated per arm as number of individuals on maximum dose Irbesatan therapy divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the BP at the End of the Study From Baseline | Study end (week 12) | Difference in systolic and diastolic BP from baseline to end of study follow-up (week 12) calculated as a mean for each study visit. |
| Proportion of Patients Who Have a Potassium of >6mmol/l, or >6.5mmol/l at Any Time During the Study | Cumulative across study follow-up, assessed at study end (week 12) | Difference in proportion of patients who have a potassium of \>6mmol/l,, or \>6.5mmol/l at any time during the study. Proportion is calculated per arm as number of individuals with a maximum potassium across study follow-up of \>6mmol/l or \>6.5mmol/l divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm. |
| Proportion of Patients Who Have a Potassium of <3.5mmol/l • | Cumulative across study follow-up, assessed at study end (week 12) | Difference in proportion of patients who have a potassium of \<3.5mmol/l at any time during the study. Proportion is calculated per arm as number of individuals with a minimum potassium of \<3.5mmol/l across study follow-up divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm. |
| Change in Potassium From Baseline at Each Time Point | At each study visit (weeks 1, 2, 4, 6, 8,12) | Difference in potassium from baseline at each study visit (weeks 1, 2, 4, 6, 8,12) calculated as a mean for each study visit. |
| Change in GFR at the End of Study From Baseline | Study end (week 12) | Difference in GFR from baseline to end of study follow-up (week 12) calculated as a mean for each study visit. |
| Frequency of Adverse Events | Study end (week 12) | A count of the number of adverse events reported in each study arm |
| Proportion of Patients Whose Glomerular Filtration Rate (GFR) Falls by >30% From the Previous Visit • | Cumulative. Calculated at each study visit. Assessed at study end (week 12). | Difference in proportion of patients with a sudden drop in GFR defined as \>30% decreased between study visits. Proportion is calculated per arm as number of individuals experiencing a sudden drop of GFR divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm. |
Countries
United Kingdom
Participant flow
Pre-assignment details
After patient enrolment, patients were checked for eligibility, then randomized to either Arm A or B if eligible. 18 participants were consented for inclusion in ORTIZ. 7 participants failed screening as they did not meet the inclusion criteria. Two participants were not randomised despite being eligible. One participant was deemed to be unable to comply with the study schedule. The other was screened and found to be eligible 2 days prior to study termination so was not randomised.
Participants by arm
| Arm | Count |
|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 3 month treatment using Sodium zirconium cyclocilicate. Doses of 5 or 10g once daily will be used. The dose will be titrated according to potassium levels performed at clinic visits
Sodium Zirconium Cyclosilicate: sachets of 5g or 10g given OD titrated to serum potassium | 4 |
| Placebo 3 month treatment using matched placebo. Doses of 5 or 10g once daily will be used. The dose will be titrated according to potassium levels performed at clinic visits
Placebo: matched placebo given titrated according to potassium at a dose to 5 or 10g | 5 |
| Total | 9 |
Baseline characteristics
| Characteristic | Sodium Zirconium Cyclosilicate (SZC) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Continuous | 57.5 years STANDARD_DEVIATION 9.5 | 58.0 years STANDARD_DEVIATION 14.2 | 57.8 years STANDARD_DEVIATION 11.6 |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Caucasian | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
| Type of Medical Histpry Diabetes | 3 participants | 5 participants | 8 participants |
| Type of Medical Histpry Hypertension | 1 participants | 3 participants | 4 participants |
| Type of Medical Histpry Kidney disease | 1 participants | 4 participants | 5 participants |
| Type of Medical Histpry Other | 2 participants | 2 participants | 4 participants |
| Type of Medical Histpry Unknown | 1 participants | 0 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 |
| other Total, other adverse events | 3 / 4 | 2 / 5 |
| serious Total, serious adverse events | 0 / 4 | 1 / 5 |
Outcome results
Primary
Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo
Difference in proportion of patients on maximum dose (300mg) Irbesartan therapy at the end of 12 weeks compared to placebo. Proportion is calculated per arm as number of individuals on maximum dose Irbesatan therapy divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.
Time frame: Study end (week 12)
Population: Patients with diabetic kidney disease
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo | Number of participants reaching maximum dose of irbesartan | 2 Participants |
| Sodium Zirconium Cyclosilicate (SZC) | Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo | Number of participants with no available data on irbesartan dose | 1 Participants |
| Sodium Zirconium Cyclosilicate (SZC) | Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo | Number of participants who did not reach maximum dose of irbesartan | 1 Participants |
| Placebo | Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo | Number of participants reaching maximum dose of irbesartan | 3 Participants |
| Placebo | Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo | Number of participants with no available data on irbesartan dose | 0 Participants |
| Placebo | Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo | Number of participants who did not reach maximum dose of irbesartan | 2 Participants |
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [-0.752, 0.552]
Secondary
Change in GFR at the End of Study From Baseline
Difference in GFR from baseline to end of study follow-up (week 12) calculated as a mean for each study visit.
Time frame: Study end (week 12)
Population: Patients with diabetic kidney disease
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Change in GFR at the End of Study From Baseline | eGFR at Baseline | 41.00 mL/min/1.73m^2 | Standard Deviation 18.49 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in GFR at the End of Study From Baseline | eGFR at 12 weeks | 35.00 mL/min/1.73m^2 | Standard Deviation 16.19 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in GFR at the End of Study From Baseline | Difference from baseline | -6.0 mL/min/1.73m^2 | Standard Deviation 2.83 |
| Placebo | Change in GFR at the End of Study From Baseline | eGFR at Baseline | 42.80 mL/min/1.73m^2 | Standard Deviation 12.58 |
| Placebo | Change in GFR at the End of Study From Baseline | eGFR at 12 weeks | 40.80 mL/min/1.73m^2 | Standard Deviation 7.79 |
| Placebo | Change in GFR at the End of Study From Baseline | Difference from baseline | -2.00 mL/min/1.73m^2 | Standard Deviation 7.28 |
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [-19.5, 11.4]
Secondary
Change in Potassium From Baseline at Each Time Point
Difference in potassium from baseline at each study visit (weeks 1, 2, 4, 6, 8,12) calculated as a mean for each study visit.
Time frame: At each study visit (weeks 1, 2, 4, 6, 8,12)
Population: Patients with diabetic kidney disease
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Change in Potassium From Baseline at Each Time Point | Week 1 | -0.58 mmol/L | Standard Deviation 0.53 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in Potassium From Baseline at Each Time Point | Week 2 | -0.03 mmol/L | Standard Deviation 0.45 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in Potassium From Baseline at Each Time Point | Week 4 | 0.10 mmol/L | Standard Deviation 0.23 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in Potassium From Baseline at Each Time Point | Week 6 | -0.10 mmol/L | Standard Deviation 0.54 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in Potassium From Baseline at Each Time Point | Week 8 | 0.05 mmol/L | Standard Deviation 0.52 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in Potassium From Baseline at Each Time Point | Week 12 | -0.50 mmol/L | Standard Deviation 0.5 |
| Placebo | Change in Potassium From Baseline at Each Time Point | Week 8 | 0.16 mmol/L | Standard Deviation 0.52 |
| Placebo | Change in Potassium From Baseline at Each Time Point | Week 1 | 0.06 mmol/L | Standard Deviation 0.42 |
| Placebo | Change in Potassium From Baseline at Each Time Point | Week 6 | 0.16 mmol/L | Standard Deviation 0.23 |
| Placebo | Change in Potassium From Baseline at Each Time Point | Week 2 | 0.24 mmol/L | Standard Deviation 0.54 |
| Placebo | Change in Potassium From Baseline at Each Time Point | Week 12 | 0.16 mmol/L | Standard Deviation 0.48 |
| Placebo | Change in Potassium From Baseline at Each Time Point | Week 4 | 0.08 mmol/L | Standard Deviation 0.36 |
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [-1.97, 0.65]
Secondary
Change in the BP at the End of the Study From Baseline
Difference in systolic and diastolic BP from baseline to end of study follow-up (week 12) calculated as a mean for each study visit.
Time frame: Study end (week 12)
Population: Patients with diabetic kidney disease
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Change in the BP at the End of the Study From Baseline | Systolic BP | -3.75 mmHg | Standard Deviation 26.8 |
| Sodium Zirconium Cyclosilicate (SZC) | Change in the BP at the End of the Study From Baseline | Diastolic BP | 1.38 mmHg | Standard Deviation 10.54 |
| Placebo | Change in the BP at the End of the Study From Baseline | Systolic BP | -28.90 mmHg | Standard Deviation 28.2 |
| Placebo | Change in the BP at the End of the Study From Baseline | Diastolic BP | -7.40 mmHg | Standard Deviation 12.75 |
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [-48.83, 99.13]
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [-22.92, 40.47]
Secondary
Frequency of Adverse Events
A count of the number of adverse events reported in each study arm
Time frame: Study end (week 12)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Frequency of Adverse Events | 6 adverse events across participants |
| Placebo | Frequency of Adverse Events | 6 adverse events across participants |
Secondary
Proportion of Patients Who Have a Potassium of <3.5mmol/l •
Difference in proportion of patients who have a potassium of \<3.5mmol/l at any time during the study. Proportion is calculated per arm as number of individuals with a minimum potassium of \<3.5mmol/l across study follow-up divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.
Time frame: Cumulative across study follow-up, assessed at study end (week 12)
Population: Patients with diabetic kidney disease
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Proportion of Patients Who Have a Potassium of <3.5mmol/l • | 0 Participants |
| Placebo | Proportion of Patients Who Have a Potassium of <3.5mmol/l • | 0 Participants |
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [0, 0]
Secondary
Proportion of Patients Who Have a Potassium of >6mmol/l, or >6.5mmol/l at Any Time During the Study
Difference in proportion of patients who have a potassium of \>6mmol/l,, or \>6.5mmol/l at any time during the study. Proportion is calculated per arm as number of individuals with a maximum potassium across study follow-up of \>6mmol/l or \>6.5mmol/l divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.
Time frame: Cumulative across study follow-up, assessed at study end (week 12)
Population: Patients with diabetic kidney disease.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Proportion of Patients Who Have a Potassium of >6mmol/l, or >6.5mmol/l at Any Time During the Study | 1 Participants |
| Placebo | Proportion of Patients Who Have a Potassium of >6mmol/l, or >6.5mmol/l at Any Time During the Study | 0 Participants |
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [-0.174, 0.674]
Secondary
Proportion of Patients Whose Glomerular Filtration Rate (GFR) Falls by >30% From the Previous Visit •
Difference in proportion of patients with a sudden drop in GFR defined as \>30% decreased between study visits. Proportion is calculated per arm as number of individuals experiencing a sudden drop of GFR divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.
Time frame: Cumulative. Calculated at each study visit. Assessed at study end (week 12).
Population: Patients with diabetic kidney disease
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Proportion of Patients Whose Glomerular Filtration Rate (GFR) Falls by >30% From the Previous Visit • | 1 Participants |
| Placebo | Proportion of Patients Whose Glomerular Filtration Rate (GFR) Falls by >30% From the Previous Visit • | 0 Participants |
Comparison: Due to the small sample size only an estimate of the difference between study arms was generated. No hypothesis tests were completed.95% CI: [-0.174, 0.674]