A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms and Renal Function in Subjects With Acute Heart Failure Syndrome and Renal Impairment Who Are Hospitalized for Volume Overload and Require Intravenous Diuretic Therapy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 1,102
- 主要终点
- effect on heart failure signs and symptoms
研究概览
简要总结
The study is being conducted to examine whether KW-3902IV will result in greater improvement in signs and symptoms of heart failure, with less treatment failure than standard therapy, when it is added to IV loop diuretics in subjects with acute heart failure syndrome and renal impairment.
详细描述
Loop diuretics are generally first line therapy in patients hospitalized with acute heart failure syndrome (AHFS). Their use far exceeds that of vasoactive agents. Tubuloglomerular feedback (TGF) is the body's compensatory response to avoid excess fluid loss, and it is activated when elevated sodium concentrations in the distal tubule are detected. TGF is proposed as a contributing factor for the observed diuretic resistance that occurs in patients with heart failure. Higher doses of diuretics are required to overcome the decreased natriuresis and reduced RBF induced by TGF. Ultimately, this action creates a vicious cycle of worsening renal function and diminished diuretic effectiveness.
The primary pharmacologic rationale for the use of KW-3902 in subjects with AHFS is its mechanism of action as an adenosine A1 receptor antagonist. TGF promotes release of adenosine, and adenosine binding to A1 receptors causes vasoconstriction of the afferent arteriole, decreased RBF, and enhanced sodium reabsorption by the proximal tubule. This action results in a decrease in GFR, diminished renal function, and sodium and water retention. Blocking adenosine A1 receptors via a selective adenosine receptor antagonist may limit sodium reabsorption by the proximal tubules without triggering TGF. It promotes vasodilation of the afferent arteriole of the glomerulus, and thus, this strategy offers the potential to overcome diuretic resistance or enhance diuretic responsiveness. It may also reduce the need for increasing diuretic doses that have been associated with worse outcomes.
The objectives of this study are to evaluate the effect of KW-3902IV in addition to intravenous (IV) loop diuretics (such as furosemide) on heart failure signs and symptoms, renal function, and safety in subjects hospitalized with AHFS, volume overload, and renal impairment, and to estimate and compare within-trial medical resource utilization and direct medical costs between patients treated with KW-3902IV versus placebo.
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)
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
- •History of heart failure of at least 14 days duration for which diuretic therapy has been prescribed
- •Hospitalized for acute heart failure syndrome requiring IV diuretic therapy.
- •Impaired renal function
排除标准
- •Acute contrast induced nephropathy
- •Ongoing or planned IV therapy for heart failure with positive inotropic agents, vasopressors, vasodilators, or mechanical support with the exception of IV nitrates
- •BNP <500 pg/mL or NT-pro-BNP <2000 pg/mL
- •Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis
- •Severe pulmonary disease
- •Significant stenotic valvular disease
- •Heart transplant recipient or admitted for cardiac transplantation
- •Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening
- •Heart failure due to significant arrhythmias
- •Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.
- •Known hepatic impairment
- •Non-cardiac pulmonary edema, including suspected sepsis
- •Allergy to soybean oil or eggs
- •History of seizure
- •Stroke within 2 years
- •History of or current brain tumor of any etiology
- •Brain surgery within 2 years
- •Encephalitis/meningitis within 2 years
- •History of penetrating head trauma
- •Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years
- •History of, or at risk for, alcohol withdrawal seizures
- •Advanced Alzheimer's disease
- •Advanced multiple sclerosis
- •Hgb <8 g/dL, Hct <25%, or the need for a blood transfusion
- •Previous exposure to KW-3902
研究组 & 干预措施
2
干预措施: rolofylline (Drug)
结局指标
主要结局
effect on heart failure signs and symptoms
时间窗: 3 Days
effect on renal function
时间窗: 3 Days
次要结局
- safety(3 Days)
- within trial medical costs compared to placebo(3 Days)