A Multi Site, Placebo Controlled, Double Blind Randomised Clinical Trial Evaluating the Effectiveness of Sodium Zirconium Cyclosilicate Versus Placebo to Enable Safe Optimisation of RASi Therapy in Patients With Diabetic Kidney Disease.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo
研究概览
简要总结
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.
详细描述
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%.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
double blind randomised clinical trial.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able and willing to provide written informed consent
- •Adults ≥ 18years old
- •Type 2 Diabetes
- •CKD defined as eGFR 25-60ml/min
- •Albuminuria with uACR measured at >33.9.mg/mmol (300mg/g)
- •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
排除标准
- •Active malignancy
- •Patients who lack capacity to give informed consent
- •GI disturbance/chronic diarrhoea/stoma
- •Subjects with a life expectancy of less than 3 months.
- •Women who are pregnant, lactating, planning to become pregnant or unwilling to use effective methods of contraception during the study.
- •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.
- •History of acute eGFR fall with RASi therapy (>30% in eGFR on initiation of RASi therapy)
- •Known hypersensitivity or previous anaphylaxis to SZC or Irbesartan
- •Hypotension: BP <120/70mm/hg at screening despite no antihypertensive agent use
- •Uncontrolled Blood pressure: BP >170/110 at screening
- •Evidence of prolonged QT on ECG QTc(f)>550msec
- •History of QT prolongation associated with other medications that required discontinuation of that medication
- •Treatment with lithium, or dual blockade with ACEi and ARB or mineralocorticoid inhibitor
- •History of congenital long QT syndrome
- •Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted
- •Current or recent (within 3 months) participation in a clinical trial involving an investigational medicinal product.
- •Current treatment with a potassium binder medication
研究组 & 干预措施
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
干预措施: Sodium Zirconium Cyclosilicate (Drug)
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
干预措施: Placebo (Drug)
结局指标
主要结局
Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo
时间窗: 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.
次要结局
- Change in GFR at the End of Study From Baseline(Study end (week 12))
- Frequency of Adverse Events(Study end (week 12))
- Change in Potassium From Baseline at Each Time Point(At each study visit (weeks 1, 2, 4, 6, 8,12))
- 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))
- Proportion of Patients Who Have a Potassium of <3.5mmol/l •(Cumulative across study follow-up, assessed at study end (week 12))
- Change in the BP at the End of the Study From Baseline(Study end (week 12))
- 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).)