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

Research output: Contribution to journalArticle

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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
Number of pages16
JournalClinical Therapeutics
Volume37
Issue number11
DOIs
Publication statusPublished - 2015 Nov 1

Fingerprint

Amlodipine
Placebos
Blood Pressure
Safety
fimasartan
Essential Hypertension
Hypertension
Therapeutics
Dizziness
Creatine Kinase
Hypotension
Headache

Keywords

  • angiotensin receptor blocker
  • calcium channel blocker
  • fimasartan
  • hypertension
  • Key words amlodipine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

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

In: Clinical Therapeutics, Vol. 37, No. 11, 01.11.2015, p. 2581-2596.

Research output: Contribution to journalArticle

Lee, HY, Kim, YJ, Ahn, T, Youn, HJ, Chull Chae, S, Seo, HS, Kim, KS, Rhee, MY, Choi, DJ, Kim, JJ, Chun, KJ, Yoo, BS, Park, JS, Oh, SK, Kim, DS, Kwan, J, Ahn, Y, Bae Park, J, Jeong, JO, Hyon, MS, Cho, EJ, Han, KR, Kim, DI, Joo, SJ, Shin, JH, Sung, KC & Jeon, ES 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, vol. 37, no. 11, pp. 2581-2596. https://doi.org/10.1016/j.clinthera.2015.02.019
Lee, Hae Young ; Kim, Yong Jin ; Ahn, Taehoon ; Youn, Ho Joong ; Chull Chae, Shung ; Seo, Hong Seog ; Kim, Ki Sik ; Rhee, Moo Yong ; Choi, Dong Ju ; Kim, Jae Joong ; Chun, Kook Jin ; Yoo, Byung Su ; Park, Jong Seon ; Oh, Seok Kyu ; Kim, Dong Soo ; Kwan, Jun ; Ahn, Youngkeun ; Bae Park, Jeong ; Jeong, Jin Ok ; Hyon, Min Soo ; Cho, Eun Joo ; Han, Kyoo Rok ; Kim, Doo Il ; Joo, Seung Jae ; Shin, Jin Ho ; Sung, Ki Chul ; Jeon, Eun Seok. / 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. In: Clinical Therapeutics. 2015 ; Vol. 37, No. 11. pp. 2581-2596.
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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.",
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T1 - 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

AU - Lee, Hae Young

AU - Kim, Yong Jin

AU - Ahn, Taehoon

AU - Youn, Ho Joong

AU - Chull Chae, Shung

AU - Seo, Hong Seog

AU - Kim, Ki Sik

AU - Rhee, Moo Yong

AU - Choi, Dong Ju

AU - Kim, Jae Joong

AU - Chun, Kook Jin

AU - Yoo, Byung Su

AU - Park, Jong Seon

AU - Oh, Seok Kyu

AU - Kim, Dong Soo

AU - Kwan, Jun

AU - Ahn, Youngkeun

AU - Bae Park, Jeong

AU - Jeong, Jin Ok

AU - Hyon, Min Soo

AU - Cho, Eun Joo

AU - Han, Kyoo Rok

AU - Kim, Doo Il

AU - Joo, Seung Jae

AU - Shin, Jin Ho

AU - Sung, Ki Chul

AU - Jeon, Eun Seok

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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.

KW - angiotensin receptor blocker

KW - calcium channel blocker

KW - fimasartan

KW - hypertension

KW - Key words amlodipine

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