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

Hae Young Lee, Yong Jin Kim, Taehoon Ahn, Ho Joong Youn, Shung Chull Chae, Hong Seog Seo, Ki Sik Kim, Moo Yong Rhee, Dong Ju Choi, Jae Joong Kim, Kook Jin Chun, Byung Su Yoo, Jong Seon Park, Seok Kyu Oh, Dong Soo Kim, Jun Kwan, Youngkeun Ahn, Jeong Bae Park, Jin Ok Jeong, Min Soo HyonEun Joo Cho, Kyoo Rok Han, Doo Il Kim, Seung Jae Joo, Jin Ho Shin, Ki Chul Sung, Eun Seok Jeon

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Abstract

Purpose 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. Findings 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%]). Implications 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.

Original languageEnglish
Pages (from-to)2581-2596.e3
JournalClinical Therapeutics
Volume37
Issue number11
DOIs
Publication statusPublished - 2015 Nov 1

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All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Lee, H. Y., Kim, Y. J., Ahn, T., Youn, H. J., Chull Chae, S., Seog Seo, H., Kim, K. S., Rhee, M. Y., Choi, D. J., Kim, J. J., Chun, K. J., Yoo, B. S., Park, J. S., Oh, S. K., Kim, D. S., Kwan, J., Ahn, Y., Bae Park, J., Jeong, J. O., ... Jeon, E. S. (2015). 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. Clinical Therapeutics, 37(11), 2581-2596.e3. https://doi.org/10.1016/j.clinthera.2015.02.019