BACKGROUND:LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension. METHODS AND RESULTS: We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients toLCI699 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.
RCT Entities:
BACKGROUND:LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension. METHODS AND 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: Scott B Hoyt; Whitney Petrilli; Clare London; Gui-Bai Liang; Jim Tata; Qingzhong Hu; Lina Yin; Chris J van Koppen; Rolf W Hartmann; Mary Struthers; Tom Wisniewski; Ning Ren; Charlene Bopp; Andrea Sok; Tian-Quan Cai; Sloan Stribling; Lee-Yuh Pai; Xiuying Ma; Joe Metzger; Andreas Verras; Daniel McMasters; Qing Chen; Elaine Tung; Wei Tang; Gino Salituro; Nicole Buist; Joe Clemas; Gaochao Zhou; Jack Gibson; Carrie Ann Maxwell; Mike Lassman; Theresa McLaughlin; Jose Castro-Perez; Daphne Szeto; Gail Forrest; Richard Hajdu; Mark Rosenbach; Yusheng Xiong Journal: ACS Med Chem Lett Date: 2015-07-17 Impact factor: 4.345
Authors: Scott B Hoyt; Min K Park; Clare London; Yusheng Xiong; Jim Tata; D Jonathan Bennett; Andrew Cooke; Jiaqiang Cai; Emma Carswell; John Robinson; John MacLean; Lindsay Brown; Simone Belshaw; Thomas R Clarkson; Kun Liu; Gui-Bai Liang; Mary Struthers; Doris Cully; Tom Wisniewski; Ning Ren; Charlene Bopp; Andrea Sok; Tian-Quan Cai; Sloan Stribling; Lee-Yuh Pai; Xiuying Ma; Joe Metzger; Andreas Verras; Daniel McMasters; Qing Chen; Elaine Tung; Wei Tang; Gino Salituro; Nicole Buist; Jeff Kuethe; Nelo Rivera; Joe Clemas; Gaochao Zhou; Jack Gibson; Carrie Ann Maxwell; Mike Lassman; Theresa McLaughlin; Jose Castro-Perez; Daphne Szeto; Gail Forrest; Richard Hajdu; Mark Rosenbach; Amjad Ali Journal: ACS Med Chem Lett Date: 2015-04-07 Impact factor: 4.345
Authors: Whitney L Petrilli; Scott B Hoyt; Clare London; Daniel McMasters; Andreas Verras; Mary Struthers; Doris Cully; Thomas Wisniewski; Ning Ren; Charlene Bopp; Andrea Sok; Qing Chen; Ying Li; Elaine Tung; Wei Tang; Gino Salituro; Ian Knemeyer; Bindhu Karanam; Joseph Clemas; Gaochao Zhou; Jack Gibson; Carrie Ann Shipley; Douglas J MacNeil; Ruth Duffy; James R Tata; Feroze Ujjainwalla; Amjad Ali; Yusheng Xiong Journal: ACS Med Chem Lett Date: 2016-11-22 Impact factor: 4.345