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

Phase 1

Conditions: Resistant hypertension
MedDRA version: 8.1 Level: LLT Classification code 10038274 Term: Refractory hypertension

Registration Number: EUCTR2006-003547-23-GB

Lead Sponsor: Gilead Sciences, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Not specified

Target Recruitment: 770

Inclusion Criteria

1. Subjects must be competent to provide written informed consent.
2. Subjects must be 35-80 years of age.
3. Subjects must have resistant systolic hypertension consistent with current clinical guidelines for the treatment of hypertension.
4. Subjects with diabetes and/or CKD must have an average sitting SBP =130 mmHg.
5. All other subjects must have an average sitting SBP =140 mmHg.
6. Subjects must be receiving, and adhering to, full doses of appropriate guideline-recommended antihypertensive drugs from three different classes of antihypertensive agents, including a diuretic.
7. Subjects must have a BMI of 20 to 43 kg/m2, inclusive. If BMI >43 kg/m2, the subject must have an upper arm circumference <42 cm at Screening (Visit 1).
8. Subjects must have an eGFR of = 30mL/min/1.73m2 at Screening (Visit 1).
9. Female subjects must be of non-childbearing potential, i.e., documented post-menopausal (cessation of regular menstrual periods) for at least 2 years or surgically sterile (i.e., hysterectomy and/or bilateral oophorectomy).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Subjects with an average sitting SBP of =180 mmHg or DBP of =110 mmHg.
2. Subjects with left ventricular (LV) systolic dysfunction.
3. Subjects with a serum ALT or AST >2xULN.
4. Subjects who have experienced a myocardial infarction, unstable angina pectoris, or a cerebrovascular accident within 6 months of the Screening Visit (Visit 1).
5. Subjects with sick sinus syndrome or second or third degree atrioventricular (AV) block, chronic atrial fibrillation or recurrent atrial tachyarrhythmia (including paroxysmal atrial tachycardia), a history of recurrent ventricular tachycardia, or symptomatic bradycardia.
6. Subjects with implanted pacemakers or an implanted cardioverter defibrillator.
7. Subjects with a historical or current diagnosis of symptomatic or asymptomatic CHF, treated or untreated.
8. Subjects with hemodynamically significant valvular heart disease.
9. Subjects with Type 1 diabetes mellitus.
10. Subjects on hemodialysis or peritoneal dialysis at the time of Screening (Visit 1) and subjects with a history of solid organ transplant (e.g., kidney, heart).
11. Subjects who have had a diagnosis or recurrence of malignancy within the past 3 years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix.
12. Subjects with sleep apnea are excluded, unless a post-treatment sleep study has confirmed treatment efficacy and there are no recordings of blood oxygen saturation (SpO2) <90% at any time during the testing period.
13. Subjects who perform alternating shift or night work.
14. Subjects treated with a central alpha-2 agonist and/or an imidazoline receptor agonist (i.e., guanfacine, clonidine, moxonidine) within 90 days of Screening.
15. Subjects who have participated in a clinical study involving another investigational drug or device within 4 weeks of the Screening Visit (Visit 1).
16. Subjects not on stable doses of all concomitant medications for a minimum of 4 weeks prior to Screening (Visit 1), and subjects treated with any protocol-specified prohibited medications (e.g. thiazolidinedione).

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<br> Primary end point(s): The co-primary endpoints are the change from baseline to Week 14 in trough sitting<br> SBP and trough sitting DBP, as measured by sphygmomanometry.<br> ;<br> Main Objective: The primary objective of this study is to determine if darusentan is effective in<br> reducing SBP and DBP in subjects who have RHTN, despite being treated with full<br> doses of three or more antihypertensive drugs, including a diuretic.<br> ;<br> Secondary Objective: Secondary objectives of this study are to examine the effect of darusentan on mean<br> 24-hour ambulatory BP, percent of subjects meeting SBP goal, and eGFR. The safety<br> and tolerability of the darusentan in the subject population will also be evaluated.<br>

Secondary Outcome Measures

Name	Time	Method

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