Pharmacodynamic Influences of Candesartan, Atenolol, Hydrochlorothiazide and Drug Combinations in Hypertensive Patients.

This study has been completed.
Sponsor:
Collaborator:
Ottawa Hospital Research Institute
Information provided by:
Institut de Recherches Cliniques de Montreal
ClinicalTrials.gov Identifier:
NCT00232882
First received: October 3, 2005
Last updated: August 30, 2013
Last verified: August 2013
  Purpose

Angiotensin receptor antagonists (ARA), beta-blockers and diuretics do not seem to confer equivalent cardiovascular protection in hard outcomes clinical trials (beta blockers inferior). These results may be explained by differences in their effects on sympathetic activity, oxidative stress, inflammation and renin angiotensin system activation.

How diuretic addition to first line therapy with ARAs and beta-blockers modulates neurohumoral and hemodynamic parameters is not well understood.

The main hypothesis of this study is that an ARA (candesartan) combined or not with a diuretic will not increase sympathetic activity as much as a beta blocker (atenolol). Secondary hypothesis are of similar nature but relate to hemodynamic parameters, oxidative stress markers, inflammatory markers, or the renin angiotensin system.

The main objective of this study is to assess and compare the effects of candesartan and atenolol and their combination with low dose diuretic therapy on the autonomic nervous system, hemodynamic parameters,on oxidative stress, on inflammatory markers, and on the renin-angiotensin system.

Protocol sponsored by Astra Zeneca canada


Condition Intervention Phase
Hypertension
Drug: Candesartan Thiazide
Drug: Atenolol Thiazide
Drug: Thiazide Candesartan
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Neurohumoral and Oxidative Influences of Candesartan, Atenolol, Hydrochlorothiazide and Drug Combinations in Essential Hypertensive Patients.

Resource links provided by NLM:


Further study details as provided by Institut de Recherches Cliniques de Montreal:

Primary Outcome Measures:
  • Plasma norepinephrine [ Time Frame: June 2007 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 1. Seated blood pressure [ Time Frame: June 2007 ] [ Designated as safety issue: No ]
  • 2. 24h ambulatory blood pressure [ Time Frame: June 2007 ] [ Designated as safety issue: No ]
  • 3. Spectral analysis of heart rate (LF, HF, LF/HF) [ Time Frame: June 2007 ] [ Designated as safety issue: No ]
  • 4. Plasma [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • a. renin [ Time Frame: december 2007 ] [ Designated as safety issue: No ]
  • b. aldosterone [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • c. angiotensin II [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • d. catecholamines [ Time Frame: June 2007 ] [ Designated as safety issue: No ]
  • e. 8-epi-isoprostane [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • f. Thiobarbituric acid reactive substances (TBARS) [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • g. nitrotyrosine [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • h. interleukin 18 [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • i. E selectine [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • j. C reactive protein [ Time Frame: December 2007 ] [ Designated as safety issue: No ]
  • k. Insulin [ Time Frame: June 2007 ] [ Designated as safety issue: No ]
  • l. glucose [ Time Frame: June 2007 ] [ Designated as safety issue: No ]
  • 5. Urine [ Time Frame: June 2007 ] [ Designated as safety issue: No ]
  • a. 8-epi-isoprostane [ Time Frame: December 2007 ] [ Designated as safety issue: No ]

Enrollment: 86
Study Start Date: December 2003
Study Completion Date: April 2006
Primary Completion Date: April 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Candesartan 16 mg for 4 weeks followed by candesartan 16 mg and hydrochlorothiazide 12.5 mg for 4 weeks
Drug: Candesartan Thiazide
Candesartan 16 mg for 4 weeks then added hydrochlorothiazide for 4 weeks
Active Comparator: 2
Atenolol 100 mg for 4 weeks followed by atenolol 100 mg + hydrochlorothiazide 12.5 mg for 4 weeks
Drug: Atenolol Thiazide
Atenolol 100 mg for 4 weeks followed by atenolol 100 mg + hydrochlorothiazide 12.5 mg for 4 weeks
Active Comparator: 3
Thiazide 25 mg for 4 weeks then added with Candesartan 16 mg
Drug: Thiazide Candesartan
Thiazide 25 mg for 4 weeks then added with Candesartan 16 mg

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Mild to moderate essential hypertension as defined by a morning mean DBP *90 mmHg and * 109 mm Hg, a mean SBP * 200 mm H for two consecutive visits (Visits 2 and 3) during the two-to-four week placebo run-in period,
  2. Ability to provide written informed consent.

Exclusion Criteria:

  1. Any woman not surgically sterile or menopausal who:

    1. has a positive urine pregnancy test at screening (Visit 1) or baseline (Visit 3)
    2. is breast feeding
  2. Pre-menopausal women (last menstruation < 1 year prior to start of run-in period) who:

    1. are not surgically sterile; and/or
    2. are of child-bearing potential and are NOT practicing acceptable means of birth control.
  3. Known or suspected secondary hypertension.
  4. Known reversible or non-reversible obstructive lung disease (e.g. asthma or COPD).
  5. Hepatic and/or renal dysfunction as defined by the following laboratory parameters:

    1. ALT or AST greater than 2.0 times the upper limit of reference range;
    2. Serum creatinine greater than 150 umol/L.
  6. Uncorrected volume depletion.
  7. NYHA functional class CHF III-IV (Refer to Appendices).
  8. Coronary heart disease needing pharmacological therapy.
  9. Stroke within the preceding six months.
  10. PTCA within the preceding three months.
  11. History of angioedema.
  12. Clinically significant sinus bradycardia below 55 beats/min. at randomization.
  13. Sustained ventricular tachycardia, atrial fibrillation, or other clinically relevant cardiac arrhythmias as determined by the clinical Investigator.
  14. Second or third degree AV block, left bundle branch block or any clinically relevant conduction abnormality as determined by the clinical Investigator.
  15. Hypertrophic obstructive cardiomyopathy, aortic stenosis, hemodynamically relevant stenosis of aortic or mitral valve.
  16. Administration of digoxin.
  17. Patients with a fasting glucose > 7.0.
  18. Use of antihypertensive agents such as diuretics, ACE inhibitors, angiotensin II antagonists, *- blockers, *-blockers, calcium channel antagonists, direct vasodilators that cannot be stopped for the trial.
  19. Administration of other non-antihypertensive medications known to affect blood pressure (e.g., oral corticosteroids, MAO inhibitors, nitrates) at any time during the trial.
  20. Chronic use of salt substitutes containing potassium chloride; potassium supplements; extreme dietary restrictions.
  21. Uncorrected sodium depletion as defined by a serum sodium level less than 135 mEq/L.
  22. Clinically significant hyperkalemia as defined by serum potassium level greater than 5.2 mEq/L. Clinically significant hypokalemia as defined by serum potassium level less than 3.0 mEq/L.
  23. Patients receiving any investigational therapy within one month of signing the informed consent form.
  24. Known hypersensitivity to any component of candesartan, atenolol or hydrochlorothiazide.
  25. Any other clinical condition which, in the opinion of the principal Investigator, would not allow safe completion of the protocol and safe administration of trial medication.
  26. Known for allergy to sulfa or heparin
  27. Blood donation in the preceding 2 months
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00232882

Locations
Canada, Quebec
Institut de Recherches Cliniques de Montréal
Montréal, Quebec, Canada, H2W 1R7
Sponsors and Collaborators
Institut de Recherches Cliniques de Montreal
Ottawa Hospital Research Institute
Investigators
Principal Investigator: Maxime Lamarre-Cliche, MD Institut de Recherches Cliniques de Montreal
  More Information

No publications provided

Responsible Party: Maxime Lamarre-Cliche, Institut de Recherches Cliniques de Montreal
ClinicalTrials.gov Identifier: NCT00232882     History of Changes
Other Study ID Numbers: D2452L00003
Study First Received: October 3, 2005
Last Updated: August 30, 2013
Health Authority: Canada: Health Canada

Keywords provided by Institut de Recherches Cliniques de Montreal:
Hypertension
Blood pressure
Antihypertensive drugs
Clinical Pharmacology
Autonomic nervous system
Renin angiotensin system
Oxidative stress
Inflammatory markers

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Candesartan
Candesartan cilexetil
Antihypertensive Agents
Atenolol
Hydrochlorothiazide
Sodium Chloride Symporter Inhibitors
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Arrhythmia Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Membrane Transport Modulators
Diuretics
Natriuretic Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on July 23, 2014