Losartan Versus Hydrochlorothiazide in Reversing Remodeling of Small Arteries in Pre-Hypertensive Pre-Diabetic Subjects

This study has been terminated.
(Few subjects recruited, sponsor withdrew support.)
Sponsor:
Collaborator:
Merck Frosst Canada Ltd.
Information provided by:
Sir Mortimer B. Davis - Jewish General Hospital
ClinicalTrials.gov Identifier:
NCT00388388
First received: October 13, 2006
Last updated: September 28, 2009
Last verified: September 2009
  Purpose

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.


Condition Intervention Phase
Pre-Hypertension
Pre-diabetes
Drug: losartan, hydrochlorothiazide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Sir Mortimer B. Davis - Jewish General Hospital:

Primary Outcome Measures:
  • 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 [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 30
Study Start Date: March 2007
Estimated Study Completion Date: December 2009
Estimated Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Losartan treatment
Drug: losartan, hydrochlorothiazide
Losartan, 50-100 mg per day, once a day, for 6 months. Hydrochlorothiazide, 12.5-25 mg per day, once a day, for 6 months.
Other Name: Cozaar, Apo-hydro
Active Comparator: 2
Hydrochlorothiazide, 12.5-25 mg per day once a day for 6 months
Drug: losartan, hydrochlorothiazide
Losartan, 50-100 mg per day, once a day, for 6 months. Hydrochlorothiazide, 12.5-25 mg per day, once a day, for 6 months.
Other Name: Cozaar, Apo-hydro

  Hide Detailed Description

Detailed Description:

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.

Thirty subjects who satisfy the study criteria will be randomized to receive once daily therapy with either losartan 50 mg or hydrochlorothiazide 12.5 mg. Subjects will take study medication once daily between 06:30 and 11:00, and be followed up in morning clinic visits, scheduled between 06:30 and 11:00. Subjects will be instructed not to take their medication on the morning of clinic visits until after the clinic evaluations have been completed. During the 6 months of treatment, subjects will have their "trough" blood pressure, heart rate (HR) and body weight measured at every clinic visit. At visits where laboratory safety tests will be done, subjects will be asked to come fasting.

All subjects will be force-titrated to losartan 100mg daily or hydrochlorothiazide 25 mg daily. However, if they develop dizziness and/or SiBPs below 100/70 mmHg, the dose may be down-titrated back to 50 mg losartan or 12.5 mg hydrochlorothiazide.

If any subjects develops SiBPs > 139/90 mmHg, open label amlodipine will be give to maintain SiBP < 139/90 mmHg, attempting however to reach the goal of SiSBP < 120 mmHg. Amlodipine will be started at a dose of 2.5mg daily and up-titrated every 4 weeks to 5 mg daily and then to 10 mg daily. As long as SiBP < 139/90 mmHg, subjects will not be discontinued from the study. Subjects whose hypertension is not adequately controlled (SiBP > 139/90 mmHg) with addition of amlodipine up-titrated to 10 mg daily, however, will be discontinued from the study.

Laboratory safety tests will be done at Weeks 4, 12, 24 of double-blind therapy (Visits 6, 8 and 9). An ECG will be repeated at the end of the study (Week 24).

The study will start at the end of 2006, last approximately 1 year. Recruitment should be completed within 6-9 months. Duration of other periods has been specified briefly above within the protocol.

  Eligibility

Ages Eligible for Study:   25 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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)

Exclusion Criteria:

  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00388388

Locations
Canada, Quebec
Cardiovascular Prevention Centre, Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Sir Mortimer B. Davis - Jewish General Hospital
Merck Frosst Canada Ltd.
Investigators
Principal Investigator: Ernesto L. Schiffrin, MD, PhD Physician-Chief, SMBD - Jewish General Hospital & Professor of Medicine, McGill University
  More Information

Additional Information:
Publications:
Responsible Party: Ernesto L. Schiffrin/Physician-in-Chief, SMBD-Jewish General Hospital, McGill University
ClinicalTrials.gov Identifier: NCT00388388     History of Changes
Other Study ID Numbers: CPC030
Study First Received: October 13, 2006
Last Updated: September 28, 2009
Health Authority: Canada: Health Canada
Canada: Ethics Review Committee

Keywords provided by Sir Mortimer B. Davis - Jewish General Hospital:
Remodeling
Resistance arteries
angiotensin receptor blocker
thiazide diuretic

Additional relevant MeSH terms:
Hypertension
Glucose Intolerance
Prediabetic State
Prehypertension
Vascular Diseases
Cardiovascular Diseases
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Diabetes Mellitus
Endocrine System Diseases
Hydrochlorothiazide
Losartan
Angiotensin Receptor Antagonists
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Anti-Arrhythmia Agents
Angiotensin II Type 1 Receptor Blockers

ClinicalTrials.gov processed this record on April 20, 2014