Double-blind, Randomized, Parallel Design Study Comparing Effectiveness of Losartan vs. Hydrochlorothiazide in Reversing or Preventing the Progression of the Remodeling of Resistance Arteries in Pre-hypertensive Pre-diabetic Subjects
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Effect of 6 months of losartan or hydrochlorothiazide on media/lumen ratio of gluteal subcutaneous resistance arteries in otherwise normal subjects who fulfill criteria for pre-hypertension and pre-diabetes
研究概览
简要总结
This randomized, double-blind, parallel group, two-centre pilot study will test the hypothesis that subjects who are otherwise healthy but fulfill the criteria for a diagnosis of pre-hypertension and pre-diabetes will have regression or reduced progression of hypertension-associated changes in their resistance arteries if their blood pressure is controlled for 6 months with losartan, whereas similar subjects whose blood pressure is equally well controlled using hydrochlorothiazide will have significantly less improvement of the changes in their resistance arteries.
详细描述
This randomized, double-blind, parallel group, two-centre pilot study will test the hypothesis that subjects who are otherwise healthy but fulfill the criteria for a diagnosis of pre-hypertension and pre-diabetes will have regression or reduced progression of hypertension-associated changes in their resistance arteries if their blood pressure is controlled for 6 months with losartan, whereas similar subjects whose blood pressure is equally well controlled using hydrochlorothiazide will have significantly less improvement of the changes in their resistance arteries.
The study will be conducted by Dr. Ernesto Schiffrin at the Cardiovascular Prevention Center, Sir Mortimer B. Davis Jewish General Hospital, McGill University, in Montreal, in association with a co-investigator at a second site, Dr. Rhian M. Touyz at the Ottawa General Hospital's Hypertension Clinic at the Riverside Campus and Kidney Research Center (University of Ottawa/Ottawa Health Research Institute). Over the past 15 years, Dr. Schiffrin has developed the gluteal subcutaneous biopsy methodology to be applied in the study. The technique has been practiced for many years (15 years) by Dr. Schiffrin, who more recently has collaborated with Dr. Touyz who used the technique together with Dr. Schiffrin before moving to Ottawa in 2005. In addition, stiffness of aorta (carotid-femoral pulse wave velocity) and endothelium-dependent hyperemic responses will be evaluated. Dr. Schiffrin and Dr. Touyz will be responsible for patient recruitment, data collection and analysis, and maintenance of study charts and patient records. Merck-Frosst Canada Ltd (MFCL) will be responsible for the study budget and the supply of medication.
The study subjects (men or women, 25 to 70 years of age) will be divided into two groups. Individuals with pre-hypertension (blood pressure = 120-139/85-90 mmHg) will be double-blindly allocated to either losartan or hydrochlorothiazide therapy respectively in groups 1 and 2. Study subjects will be assessed for their compatibility with inclusion and exclusion criteria, and subjects meeting the criteria will undergo baseline biopsies of gluteal subcutaneous resistance vessels. In addition, stiffness of aorta (carotid-femoral pulse wave velocity) and finger endothelium-dependent hyperemic responses will be evaluated. Subjects in each treatment group will receive antihypertensive therapy for 6 months, to control their blood pressure to 100-120/70-80 mmHg, and then have repeat gluteal biopsies, aortic stiffness and endothelial function measurements. The media/lumen ratio of resistance arteries 150-300 um in lumen diameter in the biopsied tissues will be determined. Previous work (1-3) has shown this parameter to be a useful marker of hypertensive vascular disease which may be modified by treatment with antihypertensive agents, particularly blockers of the renin-angiotensin system.
Subjects will give informed consent, and be medically assessed to determine whether they satisfy the inclusion and exclusion criteria. Eligible subjects will have a sitting systolic blood pressure (SiSBP) 120-139 mmHg, and be otherwise in good health. Eligible subjects will have a gluteal biopsy, and then be randomized to treatment group 1 or group 2 for 6 months.
For study purposes, SiSBP will be defined as the average of three consecutive valid readings, taken at one-minute intervals after five minutes of repose.
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
- 25 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Prehypertensive prediabetic subjects (25-70 years old) defined as otherwise normal subjects with a mean SiSBP of 120-139 mmHg and fasting blood glucose of 6.1-6.9 mmol/L or impaired glucose tolerance on oral glucose tolerance test (OGTT) at screening and after two weeks of placebo therapy (Week -2)
排除标准
- •Hypertension or clinically significant renal disease
- •Cerebrovascular accident within the past year, or current transient ischemic attacks
- •Myocardial infarction within the past year; percutaneous coronary angioplasty or coronary artery bypass surgery within last 6 months
- •Clinically significant AV conduction disturbances and/or arrhythmias (e.g. second- or third-degree AV block; sick-sinus syndrome or clinically significant bradycardia- resting heart rate < 45 beats/minute), tachyarrhythmias; clinically significant arrhythmias, presence of accessory bypass tract (e.g. Wolff-Parkinson-White syndrome)
- •Angina pectoris
- •Current or prior history of heart failure or known left ventricular ejection fraction <40%
- •History of unexplained syncope or known syncopal disorder (e.g., Stokes-Adams Syndrome)
- •Known history of hemodynamically significant obstructive valvular disease or hypertrophic cardiomyopathy
- •Use of agents that may cause alteration of blood pressure is prohibited. This includes nitrates, or alpha or beta-blockers. Calcium channel blockers are allowed as second line therapy if hypertension develops during the study Major psychotropic agents and antidepressants are not permitted
- •Cimetidine is not permitted (famotidine and ranitidine and proton pump inhibitors are allowed).
- •NSAIDs are permitted if taken on a stable regimen. Aspirin in small doses (< 1 g/day) as cardioprotective agent and acetaminophen are permitted
- •Oral or inhaled steroids, ACTH, immunosuppressants or lithium are not allowed
- •Serum creatinine concentration >200 μmol/L (adjusted for age and weight)
- •Urine dipstick or microscopic findings suggestive of significant renal or other disease.
- •Hematuria should be evaluated, the etiology established/documented, and treatment rendered as appropriate prior to entry
- •Off-treatment serum potassium concentration >5.5 mmol/L or <3.5 mmol/L
- •AST (SGOT) or ALT (SGPT) >2 x normal upper limit
- •Clinically significant laboratory values outside of the established normal range including but not limited to the following parameters: hemoglobin, platelet count or white blood cell count
- •Known hypersensitivity or contraindication to losartan or thiazide diuretics
- •History of clinically important malabsorption or gastrointestinal resection
- •Current urinary tract infection
- •Smoking 10 cigarettes or more.
- •Pregnancy or lactating females. Females of childbearing age who are not surgically sterilized and are using effective contraception may enter only if an exclusionary pregnancy test is done within 72 hours of the first double-blind dose of test agent. Pregnancy tests will then be done monthly throughout the study.
- •Vasculitis or vasculopathy: collagen-vascular diseases, chronic hepatitis B antigenemia, circulating immune complexes, complement disorders, amyloidosis, scleroderma, etc. Neoplasms, Acquired Immunodeficiency Syndrome (AIDS), or HIV positive
- •Bleeding or platelet disorder
- •Known absence of one kidney
- •Subjects abusing or who within past two years abused alcohol or other drug substances
- •Mentally or legally incapacitated subjects
- •Subjects who have participated in another investigational drug trial, including those using marketed drugs (i.e. patient has signed a consent form), within the 28 days prior to start of placebo therapy
- •Subjects who, in the opinion of the investigator, will not cooperate fully, keep appointments or are unreliable
- •Inability or unwillingness to sign the Patient Consent Form
- •Phase V of Korotkoff sounds cannot be detected
研究组 & 干预措施
1
Losartan treatment
干预措施: losartan, hydrochlorothiazide (Drug)
2
Hydrochlorothiazide, 12.5-25 mg per day once a day for 6 months
干预措施: losartan, hydrochlorothiazide (Drug)
结局指标
主要结局
Effect of 6 months of losartan or hydrochlorothiazide on media/lumen ratio of gluteal subcutaneous resistance arteries in otherwise normal subjects who fulfill criteria for pre-hypertension and pre-diabetes
时间窗: 6 months
次要结局
- Safety and tolerability of 6 month therapy with losartan or hydrochlorothiazide, and effect on media thickness, lumen diameter and vascular function of gluteal subcutaneous resistance arteries, and serum and tissue inflammatory markers in same subjects(6 months)
研究者
Ernesto L. Schiffrin
Physician-in-Chief
Sir Mortimer B. Davis - Jewish General Hospital