Official Title: “A Phase 3 Randomized, Double-Blind, Placebo- and Active-Controlled, Multi-center, Parallel Group Study to Evaluate the Safety and Efficacy of Darusentan in Subjects With Resistant Hypertension Receiving Combination Therapy With Three or More Antihypertensive Drugs, Including a Diuretic, as Compared to Guanfacine or Placebo (Protocol DAR-312)”

This is a randomized, double-blind, placebo- and active-controlled study of a new experimental drug called darusentan. Darusentan is not currently approved by the United States Food and Drug Administration (FDA), which means that a doctor cannot prescribe this drug. The purpose of this study is to determine if darusentan is effective in reducing systolic and diastolic hypertension despite treatment with full doses of three or more antihypertensive drugs, including a diuretic. Subjects will be randomized to darusentan (optimized dose), an active comparator, or placebo, administered orally. The treatment period for this trial is 14 weeks.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: August 2009

Intervention(s) in this Clinical Trial

• Drug: darusentan (LU 135252), guanfacine, and placebo
  • 1 capsule QD, PO

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • 50, 100 or 300 mg
• Active Comparator: 2
  • 1 mg
• Placebo Comparator: 3

Primary Measures

• Co-primary efficacy measures: changes from baseline in trough sitting systolic and diastolic blood pressure measured by sphygmomanometry
  • Time Frame: Week 14
    Safety Issue?: No

Secondary Measures

• Secondary efficacy measures: 1) change from baseline in mean 24-hour systolic and diastolic blood pressure measured by ABPM; 2) percent of subjects reaching systolic blood pressure goal after 14 weeks of treatment; 3) change from baseline in eGFR.
  • Time Frame: Week 14
    Safety Issue?: No

SELECTED INCLUSION CRITERIA:

• 1. Subjects who are competent to provide written consent;
• 2. Aged 35 to 80 years;
• 3. Subjects with diabetes and/or chronic kidney disease must have an average sitting systolic blood pressure greater than or equal to 130 mmHg;
• 4. All other subjects must have an average sitting systolic blood pressure greater than or equal to 140 mmHg;
• 5. Receiving and adhering to full doses of appropriate guideline-recommended antihypertensive drugs from three different classes of antihypertensive agents, including a diuretic;
• 6. Female subjects of non-childbearing potential (i.e., post-menopausal for at least 2 years or surgically sterile).

SELECTED EXCLUSION CRITERIA:

• 1. Average sitting systolic and diastolic blood pressure greater than or equal to 180 mmHg and 110 mmHg, respectively;
• 2. Subjects treated with a central alpha-2 agonist and/or imidazoline receptor agonist;
• 3. Left ventricular dysfunction;
• 4. Serum ALT or AST greater than 2 times the Upper Limit of Normal;
• 5. Subjects who have experienced myocardial infarction, unstable angina pectoris, or a cerebrovascular accident within 6 months; or sick sinus syndrome or second or third degree atrioventricular block, atrial fibrillation or recurrent atrial tachycardia, recurrent ventricular tachycardia, or symptomatic bradycardia;
• 6. Implanted pacemakers or cardioverter defibrillator;
• 7. Symptomatic CHF requiring treatment;
• 8. Hemodynamically significant valvular heart disease;
• 9. Hemodialysis or peritoneal dialysis, or history of renal transplant;
• 10. Type I diabetes mellitus;
• 11. Diagnosis or recurrence of malignancy within the past 3 years;
• 12. Sleep apnea, unless a recent sleep study demonstrated arterial oxygenation saturation greater than or equal to 90%, treated or untreated;
• 13. Subjects who perform alternating shift or night work;
• 14. Subjects who have participated in a clinical study involving another investigational drug or device within 4 weeks prior to Screening

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 35 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Gilead Sciences

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00389779

Study ID Number: Protocol DAR-312

ClinicalTrials.gov Identifier: NCT00389779

Health Authority: United States: Food and Drug Administration