PHARES Study: Management of Resistant Hypertension

February 25, 2011 updated by: Assistance Publique - Hôpitaux de Paris

Management of Resistant Hypertension -Pharmacokinetic Assessment of Different Antihypertensive Regimen -Comparison of Two Treatment Strategies: Increase Sodium Depletion or Combined Blockage of Renin-angiotensin System (RAS)

The purpose of this study is to assess the efficacy of two different treatment regimens for treating resistant hypertension previously uncontrolled with at least 3 antihypertensive treatments. The study hypothesis is that these two regimens (one based on increasing diuretics and the other based on increasing renin angiotensin system blockage) may not differ in terms of efficacy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Tested hypothesis: For essential resistant hypertension, a new regimen based on intensive RAS blockage is non inferior to the recommended regimen based on intensive sodium depletion.

Primary objective: To demonstrate non-inferiority (i.e difference between the two regimen less than 5 mmHg for the mean day-time SBP at week 12)

  • One treatment arm including irbesartan 300 mg, hydrochlorothiazide (HCTZ) 12.5mg, amlodipine 5 mg, ramipril 10mg and bisoprolol 10 mg
  • One treatment arm including irbesartan 300 mg, HCTZ 12.5mg, amlodipine 5 mg, spironolactone 25 mg, furosemide 40 mg and amiloride 5 mg.

Secondary objectives:

  • To assess clinical and biological safety and efficacy of these regimen
  • To evaluate predicted factors of controlled or uncontrolled BP
  • To evaluate compliance to treatment
  • To compare the cost of the different strategies
  • To compare the two strategies in terms of endothelial function and left ventricular diastolic filling

Study design:

  • Period 1 from week-4 to week 0 : 4-week treatment for all patients with irbesartan 300 mg, HCTZ 12.5mg, amlodipine 5 mg. At the end of this period, an ABPM will be performed: only patients with a mean day time SBP>135 and/or DBP>85 mmHg will be randomized for a further 3 months treatment
  • Period 2 from week 0 to week 4: patients will be randomized in two groups, the first one receiving spironolactone 25mg and the second one receiving ramipril 5 mg as add-on therapy (on top of the previous tri-therapy).
  • Period 3 from week 4 to week 8: Patients with BP controlled at week 4 (i.e mean home blood pressure measurement (HBPM) <135/85 mmHg at week 4) remain on the same treatment. For those uncontrolled (i.e. mean HBPM >135/85 mmHg at week 4), furosemide 20 mg will be added in the first group and ramipril will be titrated to 10 mg in the second group
  • Period 4 from week 8 to week 10: Patients with BP controlled at week 8 (i.e. mean HBPM <135/85 mmHg at week 8) remain on the same treatment. For those uncontrolled (i.e. mean HBPM >135/85 mmHg at week 8), furosemide will be titrated to 40 mg in the first group and bisoprolol 5 mg will be added in the second group.
  • Period 5 from week 10 to week 12 (end of the study): Patients with BP controlled at week 10 (i.e mean HBPM <135/85 mmHg at week 10) remain on the same treatment. For those uncontrolled (i.e mean HBPM > 135/85 mmHg at week 10), amiloride 5 mg will be added to the previous treatment in the first group and bisoprolol will be titrated to 10 mg in the second group.

Reasons for treatment discontinuation:

  • Patient decision
  • Informed consent withdrawal
  • SBP>180 mmHg or <100 mmHg (HBPM) whatever the time during the trial
  • Adverse events related to treatment or not

Study Type

Interventional

Enrollment (Actual)

180

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
    • Ile de France
      • Paris, Ile de France, France, 75015
        • Investigation Clinical Center European Georges Pompidou Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Primary hypertension
  • Resistant hypertension defined by mean day-time SBP > 135 mmHg and DBP > 85 mmHg (determined with ABPM device) after a standardized 4-week regimen including irbesartan, amlodipine and HCTZ.

Exclusion Criteria:

  • Secondary hypertension
  • Unstable angina, history of stroke or coronary heart disease (coronary by-pass or angioplasty) in the previous 3 months
  • History of cough with ACEi or gynecomastia with antialdosterones
  • Heart failure (New York Heart Association [NYHA] III-IV)
  • Contraindication to beta blockers because of bronchopathy or auriculoventricular block
  • Diabetes mellitus (type 1 or 2) with HbA1C > 8%
  • Renal failure with creatinine clearance < 40ml/min (COCKROFT evaluation)
  • Arm circumference > 42 cm

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean day-time systolic blood pressure (SBP) at week 12, measured with an average blood pressure measurement (ABPM) device
Time Frame: at week 12
Mean day-time systolic blood pressure (SBP) at week 12, measured with an average blood pressure measurement (ABPM) device
at week 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy: mean day-time diastolic blood pressure (DBP) at week 12, mean 24 hours SBP and DBP at week 12 measured with an ABPM device
Time Frame: at week 12,
hours SBP and DBP at week 12 measured with an ABPM device
at week 12,
Safety and tolerability:
Time Frame: during the study
Safety and tolerability:
during the study
During the study BP will be evaluated every 4 weeks by home blood pressure measurement [HBPM] in order to detect hypotension)
Time Frame: every 4 weeks
During the study BP will be evaluated every 4 weeks by home blood pressure measurement [HBPM] in order to detect hypotension)
every 4 weeks
Biological examinations:
Time Frame: during the study
Biological examinations:
during the study
blood and urinary electrolytes with creatinemia at week 0, 4, 8, 10 and 12
Time Frame: at week 0, 4, 8, 10 and 12
blood and urinary electrolytes with creatinemia at week 0, 4, 8, 10 and 12
at week 0, 4, 8, 10 and 12
brain natriuretic peptide (BNP), active renin, aldosterone at week 0 and 12
Time Frame: at week 0 and 12
brain natriuretic peptide (BNP), active renin, aldosterone at week 0 and 12
at week 0 and 12
Other explorations:
Time Frame: during
Other explorations:
during
Treatment compliance (study drug accounting, N-acetyl-seryl-aspartyl-lysyl-proline [Ac SDKP] for angiotensin converting enzyme inhibitor [ACEi])
Time Frame: during the study
Treatment compliance (study drug accounting, N-acetyl-seryl-aspartyl-lysyl-proline [Ac SDKP] for angiotensin converting enzyme inhibitor [ACEi])
during the study
Echocardiography (week 0 and 12)
Time Frame: week 0 and 12
Echocardiography (week 0 and 12)
week 0 and 12
Endothelial function (week 0 and 12)
Time Frame: week 0 and 12
Endothelial function (week 0 and 12)
week 0 and 12
Pharmacokinetics of drugs (week 0 and 12)
Time Frame: week 0 and 12
Pharmacokinetics of drugs (week 0 and 12)
week 0 and 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Investigators

  • Principal Investigator: Guillaume BOBRIE, MD, Assistance Publique - Hopitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2005

Primary Completion (Actual)

August 1, 2009

Study Completion (Actual)

August 1, 2009

Study Registration Dates

First Submitted

September 16, 2005

First Submitted That Met QC Criteria

September 16, 2005

First Posted (Estimate)

September 23, 2005

Study Record Updates

Last Update Posted (Estimate)

February 28, 2011

Last Update Submitted That Met QC Criteria

February 25, 2011

Last Verified

March 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P040407

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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