A Randomized, Double-blind, Placebo-controlled Escalating Dose Phase I Interaction Study to Evaluate the Pharmacokinetics, Tolerability and Pharmacodynamics of Three Dose Levels of Debio 0614 (Istaroxime) as a 24-hour Constant Rate IV Infusion in Combination With Chronic Oral Digoxin Treatment in Patients With Controlled Cardiac Failure and Decreased Left Ventricular Systolic Function
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters.
研究概览
简要总结
This study explores a potential drug-drug interaction between istaroxime and digoxin in patients with stable CHF on chronic oral digoxin treatment.
详细描述
This is a single center, randomized, double blind, placebo controlled, escalating dose phase I interaction study. The three dose levels of istaroxime or placebo will be randomized sequentially to three cohorts (I to III) of 16 patients each (12 patients on istaroxime and 4 patients on placebo). Digoxin will be administered non blinded in all patients, once daily in the morning after a standardized breakfast, continuing with previously personalized dosage schedule during the screening period, treatment period, post treatment period and follow up period. Prior to accrual of cohorts II and III, a Data Monitoring Committee (DMC) will advise on the continuation to the next istaroxime dose, based on a predetermined safety review.
This 37 day study includes a screening period (Days -21 to -1), a treatment period (Day 1), a post treatment period (Days 2-4), and a follow up period (which includes one patient visit on Day 14). Patients will be confined in the phase I research center from Day -2 to Day 4.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 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
- •Main screening inclusion criteria :
- •Signed informed consent;
- •Male or female patients ≥18 years;
- •Female patients of childbearing potential must not be pregnant;
- •Chronic stable cardiac function impairment (no change in heart failure medication over the last 3 months and without any dosage adjustment in the last 4 weeks);
- •Systolic blood pressure (SBP) of ≥ 90 mmHg and ≤ 140 mmHg;
- •LVEF ≤ 35% by any method (to be performed at screening if not measured within the last 12 months);
- •Chronic treatment (i.e. once daily dosing without interruption) with oral digoxin started at least 3 months prior to study entry and without any concomitant administration of other positive inotropic drugs;
排除标准
- •Main screening exclusion criteria :
- •Need for current or intermittent intravenous positive inotrope administration within the preceding 6 months, or hemodynamic support devices;
- •Acute coronary syndrome within the past 3 months;
- •Coronary artery bypass graft or percutaneous coronary intervention within the past 3 months;
- •Stroke within the past 6 months;
- •Atrial fibrillation or uncontrolled heart rate (HR) (> 100 beats per minute [bpm]);
- •Significant arrhythmia or second or third degree atrio-ventricular block;
- •Valvular disease as the primary cause of HF;
- •Significant ECG abnormalities as assessed by appropriately qualified physician or investigator including QTcF >450;
- •Positive testing for Human Immunodeficiency Virus (HIV), Hepatitis B and/or Hepatitis C;
- •Main randomization exclusion criteria:
- •HR > 100 bpm or < 50 bpm;
- •Serum potassium > 5.3 mmol/L or < 3.8 mmol/L and magnesium > 1.1 mmol/L or < 0.6 mmol/L,
- •TN I > ULN.
研究组 & 干预措施
1
TREATMENT 0.5 μg/kg/min
干预措施: Istaroxime (Drug)
2
TREATMENT 1.0 μg/kg/min
干预措施: Istaroxime (Drug)
3
TREATMENT 1.5 μg/kg/min
干预措施: Istaroxime (Drug)
4
PLACEBO
干预措施: Istaroxime (Drug)
结局指标
主要结局
Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters.
Pharmacokinetic endpoints : Istaroxime PK parameters: - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) plasma concentrations - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) urine concentrations
Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations
Safety endpoints: - Incidence of adverse events; - Change in vital signs; - Change in 12-lead ECG parameters; - Incidence of clinically or hemodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous EC
次要结局
未报告次要终点