Define in Preclinical Systolic Dysfunction (PSD) With Renal Dysfunction, the Cardiorenal and Humoral Actions of Chronic Type V Phosphodiesterase (PDEV) Inhibition
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Mayo Clinic
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Change in Urinary Sodium Excretion
研究概览
简要总结
To determine the effect of 12 weeks of chronic PDEV inhibition with Tadalafil versus placebo on basal cardiorenal and humoral function and on the integrated cardiorenal and humoral response to acute sodium loading in subjects with preclinical systolic dysfunction (PSD) and renal (kidney) dysfunction.
详细描述
At the consent visit a blood draw will be done also a the 6 minute walk will be done to determine eligibility and a physical exam along with vital signs, height and weight will be done. Twenty-four hour urine collection will be obtained one day prior to the active study day.
Prior to initiation of the study, subjects will be stabilized for at least one week on a no added salt diet (120 milliequivalents of sodium/salt per day (mEq Na/day) which will be maintained throughout the study period.
Subjects will be admitted to the Clinical Research Unit (CRU)on the evening before the active study day. They will be able to order a no-added salt meal and will not have anything to eat after midnight until the last renal clearance blood draw the next day. Bladder scan will be carried out to assess for urine retention. On the active study day, subjects take their medications upon awakening, however, diabetics will hold their diabetic medications until after the last renal clearance test then they will be able to order a regular diet meal and take their diabetic medications. Subjects will be asked to drink 5ml/Kg (milliliters per kilogram of body weight) of water to insure sufficient urinary flow. A priming dose (calculated according to body size) of Iothalamate, to measure glomerular filtration rate (GFR) and para-amino-hippurate (PAH) to measure effective renal plasma flow (ERPF) is infused, followed by a constant rate IV sustaining dose (calculated according to estimated kidney function) of Iothalamate or PAH. The subjects will be asked to empty their bladder spontaneously every thirty minutes. Throughout the study, at the end of each 30-minute clearance period, subjects will be asked to drink an amount of water equivalent to the sum of the blood losses and the urinary flow. After an equilibration period of 45 minutes, a 30-minute baseline renal clearance will be carried out.
Blood pressure will be measured at 20-minute intervals by using automatic blood pressure cuff, and heart rate will be continuously monitored by electrocardiography. Echocardiography will be performed during these baseline clearances to determine left atrial (LA) and Left Ventricular (LV)volumes and systolic and diastolic function.
After the baseline clearance the acute saline load will be administered (normal saline 0.9% 0.25 ml/kg/min for 1 hour). During the 1 hour saline load, one 30-minute clearance (as outlined above) will be repeated with the subjects in supine position after which a second 30-minute clearance will be repeated with the subject sitting or the head of the bed up. As above, blood samples are collected midway during each clearance and urine samples are obtained every 30 minutes. Echocardiography will be repeated immediately after the end of the saline infusion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 21 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A total of 39 patients with PSD as defined by an ejection fraction of less than 40%, no clinical signs or symptoms of congestive heart failure, a minimal distance on 6-minute walk of equal or >450 meters will be recruited and calculated creatinine clearance of equal or less than 90 ml/min and greater than 30 ml/min, using the (MDRD-measurement of renal dysfunction, formula) assessed within the past 24 months. If the subject is not able to walk 450 meters due to pain in hips and knees and not fatigue or shortness of breath than they will still qualify for the protocol.
排除标准
- •Current or anticipated future need for nitrate therapy
- •Systolic blood pressure < 90 mmHg or > 180 mm Hg
- •Diastolic blood pressure < 40 mmHg or > 100 mmHg
- •Patients taking alpha antagonists or cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, erythromycin, saquinavir, cimetidine or serum proteases inhibitors for HIV) who cannot be taken off these medications for the duration of the study.
- •Patients taking the following selective alpha blockers and who are unable to stop for the duration of the study;
- •Alfuzosin
- •Doxazosin
- •Tamsulosin
- •Terazosin
- •Silodosin
- •Patients with retinitis pigmentosa, previous diagnosis of nonischemic optic neuropathy, untreated proliferative retinopathy or unexplained visual disturbance
- •Patients with sickle cell anemia, multiple myeloma, leukemia or penile deformities placing them at risk for priapism (angulation, cavernosal fibrosis or Peyronie's disease)
- •Patients with an allergy to iodine.
- •Patients on PDEV inhibition for pulmonary hypertension
- •Patients on PDEV inhibition for erectile dysfunction who are not willing to stop the medication for the duration of the study
- •Valve disease (> moderate aortic or mitral stenosis; > moderate aortic or mitral regurgitation)
- •Obstructive Hypertrophic cardiomyopathy
- •Infiltrative or inflammatory myocardial disease (amyloid, sarcoid)
- •Pericardial disease
- •Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent
- •Severe congenital heart diseases
- •Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening
- •Second or third degree heart block without a permanent cardiac pacemaker
- •Stroke within 3 months of screening or other evidence of significantly compromised Central Nervous System (CNS) perfusion
- •Hemoglobin <9 g/dL
- •Patients with severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal)
- •Serum sodium of < 125 mEq/dL or > 150 mEq/dL
- •Serum potassium of < 3.2 mEq/dL or > 5.9 mEq/dL
- •Prior diagnosis of intrinsic renal diseases including renal artery stenosis of > 50%
- •Peritoneal or hemodialysis within 90 days or anticipation that dialysis or ultrafiltration of any form will be required during the study period
- •Less than 21 years of age
- •Pregnant or nursing women.
- •Women of child bearing potential who do not have a negative pregnancy test at study entry and who are not using effective contraception
- •Non-cardiac condition limiting life expectancy to less than one year, per physician judgment
- •Other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data
- •Received an investigational drug within 1 month prior to dosing
- •In the opinion of the investigator is unlikely to comply with the study protocol or is unsuitable for any reasons
研究组 & 干预措施
Tadalafil
Subject will receive Tadalafil daily for a total of 12 weeks
干预措施: Tadalafil (Drug)
Placebo
Subject will receive Placebo daily for a total of 12 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Change in Urinary Sodium Excretion
时间窗: Baseline, 12 weeks
Change in total urinary sodium excretion as measured by MEq/min
次要结局
- Change in Glomerular Filtration Rate (GFR)(Baseline, 12 weeks)
- Change in Urinary Cyclic Guanosine 3',5'-Monophosphate (cGMP) Hormone Excretion(Baseline, 12 weeks)
研究者
Horng Chen
MD, Professor of Medicine
Mayo Clinic