DORADO - Fixed Doses of Darusentan as Compared to Placebo in Resistant Hypertension

Study Overview
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Brief Summary
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This is a research study of a new experimental drug called darusentan. Darusentan is not currently approved by the U.S. Food and Drug Administration (FDA) for use in the United States, which means that a doctor cannot prescribe this drug. The purpose of this study is to determine if darusentan is effective in reducing systolic blood pressure in subjects with resistant systolic hypertension, despite treatment with full doses of three or more antihypertensive drugs, including a diuretic.

Official Title
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DORADO - A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Parallel Group Study to Evaluate the Efficacy and Safety of Fixed Doses of Darusentan in Subjects With Resistant Systolic Hypertension Receiving Combination Therapy With Three or More Antihypertensive Drugs, Including a Diuretic (Protocol DAR-311)

Conditions
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Hypertension

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


Participation Criteria
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Eligibility Criteria
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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 a mean systolic blood pressure ≥130 mmHg All other subjects must have a mean systolic blood pressure ≥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 lest 2 years; surgically sterile) Exclusion Criteria: Average sitting systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg Serum ALT or AST >2 x the upper limit of the normal range (ULN) Subjects who have experienced myocardial infarction, unstable angina pectoris, or a cerebrovascular accident (CVA) within 6 month; or sick sinus syndrome or second or third degree atrioventricular block, atrial fibrillation or recurrent atrial tachyarrhythmia, recurrent ventricular tachycardia, or symptomatic bradycardia Implanted pacemakers or implanted cardioverter defibrillator (ICD) Symptomatic congestive heart failure requiring treatment Hemodynamically significant valvular heart disease Type I diabetes mellitus Hemodialysis or peritoneal dialysis; or history of renal transplant Diagnosis or recurrence of malignancy within the past 3 years Sleep apnea, unless a recent sleep study demonstrates arterial oxygen saturation greater than or equal to 90% 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 |
| --- | --- |
| 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>|
| Experimental: Darusentan 50 mg<br>Placebo to match darusentan for 2-week placebo run-in period, followed by darusentan 50 mg administered orally once daily for 14 weeks | Drug: Darusentan<br>* Darusentan administered orally once daily<br>* Other names: LU 135252;Drug: Darusentan Placebo<br>* Placebo to match darusentan administered orally once daily<br>|
| Experimental: Darusentan 100 mg<br>Placebo to match darusentan for 2-week placebo run-in period, followed by darusentan 100 mg administered orally once daily for 14 weeks | Drug: Darusentan<br>* Darusentan administered orally once daily<br>* Other names: LU 135252;Drug: Darusentan Placebo<br>* Placebo to match darusentan administered orally once daily<br>|
| Experimental: Darusentan 300 mg<br>Placebo to match darusentan for 2-week placebo run-in period, followed by darusentan 300 mg administered orally once daily for 14 weeks | Drug: Darusentan<br>* Darusentan administered orally once daily<br>* Other names: LU 135252;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 |
| --- | --- | --- |
| Change from baseline in mean 24-hour systolic and diastolic ambulatory blood pressure |  | Baseline to Week 14 | 
| Percentage of subjects to reach systolic blood pressure goal |  | Week 14 | 
| Change from baseline in estimated glomerular filtration rate (eGFR) |  | Baseline to Week 14 |