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PHARES Study: Management of Resistant Hypertension

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ClinicalTrials.gov Identifier: NCT00224549
Recruitment Status : Completed
First Posted : September 23, 2005
Last Update Posted : February 28, 2011
Sponsor:
Information provided by:
Assistance Publique - Hôpitaux de Paris

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hypertension Drug: irbesartan, amlodipine and hydrochlorothiazide Phase 4

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : April 2005
Actual Primary Completion Date : August 2009
Actual Study Completion Date : August 2009

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Arms and Interventions
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Intervention Details:
  • Drug: irbesartan, amlodipine and hydrochlorothiazide
    irbesartan, amlodipine and hydrochlorothiazide

Outcome Measures
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Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. Safety and tolerability: [ Time Frame: during the study ]
    Safety and tolerability:

  3. 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)

  4. Biological examinations: [ Time Frame: during the study ]
    Biological examinations:

  5. 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

  6. 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

  7. Other explorations: [ Time Frame: during ]
    Other explorations:

  8. 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])

  9. Echocardiography (week 0 and 12) [ Time Frame: week 0 and 12 ]
    Echocardiography (week 0 and 12)

  10. Endothelial function (week 0 and 12) [ Time Frame: week 0 and 12 ]
    Endothelial function (week 0 and 12)

  11. Pharmacokinetics of drugs (week 0 and 12) [ Time Frame: week 0 and 12 ]
    Pharmacokinetics of drugs (week 0 and 12)


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00224549


Locations
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France
Investigation Clinical Center European Georges Pompidou Hospital
Paris, Ile de France, France, 75015
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Guillaume BOBRIE, MD Assistance Publique - Hôpitaux de Paris
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Zakia IDIR, Department of Clinical Research of developpement
ClinicalTrials.gov Identifier: NCT00224549    
Other Study ID Numbers: P040407
First Posted: September 23, 2005    Key Record Dates
Last Update Posted: February 28, 2011
Last Verified: March 2007
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Resistant hypertension
Combined diuretic therapy
Combined RAS blockers
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Amlodipine
Hydrochlorothiazide
Irbesartan
Antihypertensive Agents
Calcium Channel Blockers
Membrane Transport Modulators
 Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents
Diuretics
Natriuretic Agents
Sodium Chloride Symporter Inhibitors
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists