title: Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial.
abstract: BACKGROUND
  LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension.
  
  
  RESULTS
  We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients to LCI699 0.25 mg once daily (n=92), 0.5 mg once daily (n=88), 1.0 mg once daily (n=86), and 0.5 mg twice daily (n=97); eplerenone 50 mg twice daily (n=84); or placebo (n=77) for 8 weeks. Adrenocorticotropic hormone (250 μg IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-β-hydroxylase. Reductions in clinic diastolic blood pressure were significant for LCI699 1.0 mg (-7.1 mm Hg; P=0.0012) and eplerenone 50 mg twice daily (-7.9 mm Hg; P<0.0001) compared with placebo (-2.6 mm Hg) but not other doses of LCI699. Significant reductions in clinic systolic blood pressure were observed with all doses of LCI699 (P<0.005 or better) and eplerenone (P<0.0001). All doses of LCI699 significantly reduced 24-hour ambulatory blood pressure compared with placebo (P<0.01). Adrenocorticotropic hormone stimulation of cortisol was suppressed in ≈20% of subjects receiving LCI699 at a total daily dose of 1.0 mg. Safety and tolerability were similar among LCI699, placebo, and eplerenone.
  
  
  CONCLUSIONS
  Aldosterone synthase inhibition with LCI699 significantly lowered clinic and ambulatory blood pressure. A minority of subjects developed blunted adrenocorticotropic hormone-stimulated release of cortisol. These results support additional research to evaluate use of aldosterone synthase inhibition in primary hypertension and/or patients characterized by aldosterone excess. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00758524.
authors: Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA. dcalhoun@uab.edu
authors: David A
authors: DA
authors: Calhoun
authors: William B
authors: WB
authors: White
authors: Henry
authors: H
authors: Krum
authors: Weinong
authors: W
authors: Guo
authors: Georgina
authors: G
authors: Bermann
authors: Angelo
authors: A
authors: Trapani
authors: Martin P
authors: MP
authors: Lefkowitz
authors: Joël
authors: J
authors: Ménard
mesh_terms: D000324:Adrenocorticotropic Hormone; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000450:Aldosterone / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006728:Hormones; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012083:Renin / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D006728:Hormones; D010919:Placebos; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D019405:Cytochrome P-450 CYP11B2; D012083:Renin; D006854:Hydrocortisone