DORADO-AC - Optimized Doses of Darusentan as Compared to an Active Control in Resistant Hypertension

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Darusentan
* Drug: Guanfacine
* Drug: Darusentan Placebo


Participation Criteria
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Eligibility Criteria
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SELECTED INCLUSION CRITERIA: Subjects who are competent to provide written consent; Aged 35 to 80 years; Subjects with diabetes and/or chronic kidney disease must have an average sitting systolic blood pressure greater than or equal to 130 mmHg; All other subjects must have an average sitting systolic blood pressure greater than or equal to 140 mmHg; Receiving and adhering to full doses of appropriate guideline-recommended antihypertensive drugs from three different classes of antihypertensive agents, including a diuretic; Female subjects of non-childbearing potential (i.e., post-menopausal for at least 2 years or surgically sterile). SELECTED EXCLUSION CRITERIA: Average sitting systolic and diastolic blood pressure greater than or equal to 180 mmHg and 110 mmHg, respectively; Subjects treated with a central alpha-2 agonist and/or imidazoline receptor agonist; Left ventricular dysfunction; Serum ALT or AST greater than 2 times the Upper Limit of Normal; 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; Implanted pacemakers or cardioverter defibrillator; Symptomatic congestive heart failure requiring treatment; Hemodynamically significant valvular heart disease; Hemodialysis or peritoneal dialysis, or history of renal transplant; Type I diabetes mellitus; Diagnosis or recurrence of malignancy within the past 3 years; Sleep apnea, unless a recent sleep study demonstrated arterial oxygenation saturation greater than or equal to 90%, treated or untreated; Subjects who perform alternating shift or night work; Subjects who have participated in a clinical study involving another investigational drug or device within 4 weeks prior to Screening

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darusentan<br>Placebo to match darusentan for 2-week placebo run-in period, followed by darusentan capsules titrated to an optimal dose of 50 mg, 100 mg, or 300 mg administered orally once daily for 14 weeks | Drug: Darusentan<br>* Darusentan capsules administered orally once daily<br>* Other names: LU 135252;Drug: Darusentan Placebo<br>* Placebo to match darusentan administered orally once daily<br>|
| Active Comparator: Guanfacine<br>Placebo to match darusentan for 2-week placebo run-in period, followed by guanfacine 1 mg capsules administered orally once daily for 14 weeks | Drug: Guanfacine<br>* Guanfacine capsules administered orally once daily<br>Drug: Darusentan Placebo<br>* Placebo to match darusentan administered orally once daily<br>|
| Placebo Comparator: Darusentan Placebo<br>Placebo to match darusentan for 2-week placebo run-in period, followed by placebo to match darusentan administered orally once daily for 14 weeks | Drug: Darusentan Placebo<br>* Placebo to match darusentan administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in trough sitting systolic and diastolic blood pressure measured by sphygmomanometry |  | Baseline to Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects reaching systolic blood pressure goal after 14 weeks of treatment |  | Week 14 | 
| Change from baseline in mean 24-hour systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) |  | Baseline to Week 14 | 
| Change from baseline in estimated glomerular filtration rate (eGFR) |  | Baseline to Week 14 |