title: A Randomized, Multicenter, Double-blind, Placebo-controlled, 3 × 3 Factorial Design, Phase II Study to Evaluate the Efficacy and Safety of the Combination of Fimasartan/Amlodipine in Patients With Essential Hypertension.
abstract: OBJECTIVE
  The objective of this study was to evaluate the efficacy and safety of a fimasartan/amlodipine combination in patients with hypertension and to determine the optimal composition for a future single-pill combination formulation.
  
  
  METHODS
  This Phase II study was conducted by using a randomized, multicenter, double-blind, placebo-controlled, 3 × 3 factorial design. After a 2-week placebo run-in period, eligible hypertensive patients (with a sitting diastolic blood pressure [SiDBP] between 90 and 114 mm Hg) were randomized to treatment. They received single or combined administration of fimasartan at 3 doses (0, 30, and 60 mg) and amlodipine at 3 doses (0, 5, and 10 mg) for 8 weeks. The primary efficacy end point was the change in SiDBP from baseline and at week 8; secondary end points included the change in SiDBP from baseline and at week 4 and the changes in sitting systolic blood pressure from baseline and at weeks 4 and 8. Treatment-emergent adverse events (AEs) were also assessed.
  
  
  RESULTS
  420 Korean patients with mild to moderate hypertension were randomly allocated to the 9 groups. Mean (SD) SiDBP changes in each group after 8 weeks were as follows: placebo, -6.0 (8.5) mm Hg; amlodipine 5 mg, -10.6 (9.2) mm Hg; amlodipine 10 mg, -15.9 (7.2) mm Hg; fimasartan 30 mg, -10.1 (9.1) mm Hg; fimasartan 60 mg, -13.0 (10.0) mm Hg; fimasartan 30 mg/amlodipine 5 mg, -16.2 (8.5) mm Hg; fimasartan 30 mg/amlodipine 10 mg, -19.5 (7.5) mm Hg; fimasartan 60 mg/amlodipine 5 mg, -16.6 (6.9) mm Hg; and fimasartan 60 mg/amlodipine 10 mg, -21.5 (8.3) mm Hg. All treatment groups produced significantly greater reductions in blood pressure compared with the placebo group. In addition, all combination treatment groups had superior reductions in blood pressure compared with the monotherapy groups. In the combination treatment groups, doubling fimasartan dose in the given dose of amlodipine did not show further BP reduction, whereas doubling amlodipine dose showed significantly further BP reduction in the given dose of fimasartan. During the study period, 75 (17.9%) of 419 patients experienced 110 AEs. Ninety-five AEs were mild, 9 were moderate, and 6 were severe in intensity. Eight patients discontinued the study due to AEs. There was no significant difference in incidence of AEs among groups (P = 0.0884). The most common AE was headache (12 patients [2.9%]), followed by dizziness (11 patients [2.6%]) and elevated blood creatine phosphokinase levels (6 patients [1.4%]).
  
  
  CONCLUSIONS
  Fimasartan combined with amlodipine produced superior blood pressure reductions and low levels of AEs compared with either monotherapy. Therefore, a single-pill combination with fimasartan 60 mg/amlodipine 10 mg will be developed. ClinicalTrials.gov: NCT01518998.
authors: Seoul National University Hospital, Seoul, Republic of Korea.
authors: Hae-Young
authors: HY
authors: Lee
authors: Seoul National University Hospital, Seoul, Republic of Korea.
authors: Yong-Jin
authors: YJ
authors: Kim
authors: Gachon University Gil Medical Center, Incheon, Republic of Korea.
authors: Taehoon
authors: T
authors: Ahn
authors: Catholic University of Korea, Seoul St. Mary׳s Hospital, Seoul, Republic of Korea.
authors: Ho-Joong
authors: HJ
authors: Youn
authors: Kyungpook National University Hospital, Daegu, Republic of Korea.
authors: Shung
authors: S
authors: Chull Chae
authors: Korea University Guro Hospital, Seoul, Republic of Korea.
authors: Hong
authors: H
authors: Seog Seo
authors: Daegu Catholic University Medical Center, Daegu, Republic of Korea.
authors: Ki-Sik
authors: KS
authors: Kim
authors: Dongguk University Ilsan Hospital, Ilsan, Republic of Korea.
authors: Moo-Yong
authors: MY
authors: Rhee
authors: Seoul National University Bundang Hospital, Sungnam, Busan, Republic of Korea.
authors: Dong-Ju
authors: DJ
authors: Choi
authors: Asan Medical Center, Seoul, Republic of Korea.
authors: Jae-Joong
authors: JJ
authors: Kim
authors: Pusan University Yangsan Hospital, Busan, Republic of Korea.
authors: Kook-Jin
authors: KJ
authors: Chun
authors: Wonju Christian Hospital, Wonju, Republic of Korea.
authors: Byung-Su
authors: BS
authors: Yoo
authors: Yeungnam University Medical Center, Daegu, Republic of Korea.
authors: Jong-Seon
authors: JS
authors: Park
authors: Wonkwang University School of Medicine and Hospital, Iksan, Republic of Korea.
authors: Seok-Kyu
authors: SK
authors: Oh
authors: Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors: Dong-Soo
authors: DS
authors: Kim
authors: Inha University Hospital, Incheon, Republic of Korea.
authors: Jun
authors: J
authors: Kwan
authors: Chonnam National University Hospital, Gwangju, Republic of Korea.
authors: Youngkeun
authors: Y
authors: Ahn
authors: Cheil General Hospital, Seoul, Republic of Korea.
authors: Jeong
authors: J
authors: Bae Park
authors: Chungnam National University Hospital, Daegu, Republic of Korea.
authors: Jin-Ok
authors: JO
authors: Jeong
authors: Soonchunhyang University Hospital, Seoul, Republic of Korea.
authors: Min-Soo
authors: MS
authors: Hyon
authors: Catholic University of Korea, St. Paul׳s Hospital, Seoul, Republic of Korea.
authors: Eun-Joo
authors: EJ
authors: Cho
authors: Kangdong Sacred Heart Hospital, Seoul, Republic of Korea.
authors: Kyoo-Rok
authors: KR
authors: Han
authors: Inje University Haeundae Paik Hospital, Busan, Republic of Korea.
authors: Doo-Il
authors: DI
authors: Kim
authors: Jeju University Hospital, Jeju, Republic of Korea.
authors: Seung-Jae
authors: SJ
authors: Joo
authors: Hanyang University Hospital, Seoul, Republic of Korea.
authors: Jin-Ho
authors: JH
authors: Shin
authors: Kangbuk Samsung Hospital, Seoul, Republic of Korea.
authors: Ki-Chul
authors: KC
authors: Sung
authors: Samsung Medical Center, Seoul, Republic of Korea. Electronic address: eunseok.jeon@samsung.com.
authors: Eun-Seok
authors: ES
authors: Jeon
mesh_terms: D000328:Adult; D000368:Aged; D017311:Amlodipine / Q000008:administration & dosage*; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D000075222:Essential Hypertension; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage*; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D011743:Pyrimidines; D013777:Tetrazoles; D017311:Amlodipine; C558933:fimasartan
keywords: amlodipine; angiotensin receptor blocker; calcium channel blocker; fimasartan; hypertension