A Randomized, Double-blind, Multicenter, Phase III Study to Evaluate the Efficacy and Safety of Fimasartan/Amlodipine Combined Therapy Versus Fimasartan Monotherapy in Patients With Essential Hypertension Unresponsive to Fimasartan Monotherapy.

The goal of this study was to evaluate whether the blood pressure-lowering efficacy of fimasartan/amlodipine combination therapy was superior to that of fimasartan monotherapy after 8 weeks of treatment in patients with hypertension who had failed to respond adequately to fimasartan monotherapy. This trial was a randomized, double-blind, multicenter, Phase III clinical study. Patients who failed to respond after 4 weeks of treatment with 60 mg daily of fimasartan (sitting systolic blood pressure [SiSBP]) ≥140 mm Hg) were randomized to receive either daily fimasartan 60 mg or fimasartan/amlodipine 60 mg/10 mg. The primary efficacy end point was the change in SiSBP from baseline to week 8. Secondary end points included the change in SiSBP from baseline to week 4, the changes in sitting diastolic blood pressure from baseline to weeks 4 and 8, and the response rate (SiSBP <140 mm Hg or decrease in SiSBP ≥20 mm Hg) or control rate (SiSBP <140 mm Hg) at week 8. Treatment-emergent adverse events were also assessed. Of 143 patients randomized to treatment, 137 patients who had available efficacy data were analyzed. The mean age of patients was 59.1 (8.9) years, and 100 (73.0%) were male. Baseline SiSBP and sitting diastolic blood pressure were 150.6 (9.2) mm Hg and 91.7 (8.6) mm Hg, respectively. In the fimasartan/amlodipine combination group, a greater reduction in SiSBP from baseline to week 8 was observed compared with the fimasartan group (7.8 [13.3] mm Hg in the fimasartan group vs 20.5 [14.6] mm Hg in the fimasartan/amlodipine group; P < 0.0001). This reduction was observed after 4 weeks. The mean SiSBP changes from baseline to week 4 were 8.1 (15.8) mm Hg in the fimasartan group and 20.1 (14.7) mm Hg in the fimasartan/amlodipine group (P < 0.0001). At week 8, the response rate was significantly higher in the fimasartan/amlodipine (82.1%) group than in the fimasartan (32.9%) group (P < 0.0001). The control rate at week 8 was also higher in the fimasartan/amlodipine (79.1%) group than in the fimasartan (31.4%) group (P < 0.0001). Adverse drug reactions were observed in 9 patients (6.3%), with no significant differences between treatment groups. There were no serious adverse events associated with the study drugs. Fimasartan/amlodipine combination therapy exhibited superior efficacy in reducing blood pressure, with no increase in adverse drug reactions, compared with fimasartan monotherapy. ClinicalTrials.gov identifier: NCT02152306.

Kim KI ，Shin MS ，Ihm SH ，Youn HJ ，Sung KC ，Chae SC ，Nam CW ，Seo HS ，Park SM ，Rhee MY ，Kim MH ，Cha KS ，Kim YJ ，Kim JJ ，Chun KJ ，Yoo BS ，Park S ，Shin ES ，Kim DS ，Il Kim D ，Kim KH ，Joo SJ ，Jeong JO ，Shin J ，Kim CH ... -  《-》

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.

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. 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. 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%]). 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.

Lee HY ，Kim YJ ，Ahn T ，Youn HJ ，Chull Chae S ，Seog Seo H ，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 ... -  《-》

Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, phase III clinical study.

The standard 60-mg dose of fimasartan, a newly developed selective angiotensin II receptor blocker, is effective and safe for use in patients with mild to moderate hypertension. This study aimed to compare the efficacy and safety of low-dose (30 mg) fimasartan and placebo or valsartan (80 mg) for 8 weeks in patients with mild to moderate hypertension. In this randomized trial, 293 patients (219 men; mean age, 54.24 [9.77] years) with mild to moderate hypertension were enrolled. After randomization to receive 30-mg fimasartan (n = 115), placebo (n = 117), or 80-mg valsartan (n = 61), the treatment dose was kept constant without dose escalation for 8 weeks. The primary end point was improvement in sitting diastolic blood pressure (SiDBP) from baseline to 8 weeks that was compared between treatments with low-dose fimasartan and placebo. The secondary end point was the overall efficacy and safety of low-dose fimasartan compared with that of placebo or valsartan. At week 8, SiDBP changed by -9.93 (8.86) mm Hg in the fimasartan group and by -2.08 (9.47) mm Hg in the placebo group, which indicated significant antihypertensive efficacy (P < 0.0001). Efficacy was shown at week 4 as measured by SiDBP (-9.96 [7.73] vs -2.27 [7.85] mm Hg; P < 0.0001) or sitting systolic blood pressure (SiSBP) (-16.18 [14.44] vs -1.95 [13.48] mmHg; P < 0.0001) and at week 8 as determined by SiSBP (-15.35 [16.63] vs -2.30 [14.91] mm Hg; P < 0.0001). The fimasartan group exhibited more potent antihypertensive efficacy than the valsartan group both at week 4 (SiDBP, -9.96 [7.73] vs -6.53 [9.58] mm Hg [P = 0.0123]; SiSBP, -16.18 [14.4] vs -7.65 [12.89] mm Hg [P = 0.0002]) and at week 8 (SiDBP, -9.93 [8.86] vs -5.47 [8.96] mm Hg [P = 0.0021]; SiSBP, -15.35 [16.63] vs -7.49 [13.68] mm Hg [P = 0.0021]). Most treatment-emergent adverse events (TEAEs) were mild (89 of 95), and there were no serious TEAEs. The incidence of TEAEs was 19.1% in the fimasartan group, 22.6% in the placebo group, and 13.6% in the valsartan group, with no significant differences. Low-dose fimasartan (30 mg) was well tolerated during the study period with no significant TEAEs. Low-dose fimasartan had an effective blood pressure-lowering effect that was greater than that of 80-mg valsartan in patients with mild to moderate hypertension. ClinicalTrials.gov identifier: NCT01672476.

Youn JC ，Ihm SH ，Bae JH ，Park SM ，Jeon DW ，Jung BC ，Park TH ，Lee NH ，Song JM ，Yoon YW ，Shin ES ，Sung KC ，Jung IH ，Pyun WB ，Joo SJ ，Park WJ ，Shin JH ，Kang SM ... -  《-》

I-ADD study: assessment of efficacy and safety profile of irbesartan/amlodipine fixed-dose combination therapy compared with irbesartan monotherapy in hypertensive patients uncontrolled with irbesartan 150 mg monotherapy: a multicenter, phase III, prospec

Hypertension guidelines recommend the use of 2 agents with synergistic action when >1 agent is needed to achieve blood pressure goals. Newer antihypertensive treatment combinations include fixed-dose combinations of an angiotensin receptor blocker and a calcium channel blocker. The I-ADD study aimed to demonstrate whether the antihypertensive efficacy of fixed-dose combination irbesartan 300 mg/amlodipine 5 mg (I300/A5) was superior to that of irbesartan (I300) monotherapy in lowering home systolic blood pressure after 10 weeks' treatment. The I-ADD study was a 10-week, multicenter, Phase III, prospective, randomized, parallel-group, open-label with blinded-end point study. The main inclusion criterion was essential uncontrolled hypertension (systolic blood pressure ≥145 mm Hg at office after at least 4 weeks of irbesartan 150 mg [I150] monotherapy administered once daily). Patients continued to receive I150 for 7 to 10 days and were randomized to either monotherapy with I150 for 5 weeks then I300 for the next 5 weeks, or to a fixed-dose combination therapy (I150/A5, then I300/A5). Safety profile was assessed by recording adverse events reported by patients or observed by the investigator. Following enrollment, 325 patients were randomized to treatment, and 320 (mean [SD] age, 56.7 [11.4] years; 41% male) were included in the intention-to-treat analysis: 155 patients treated with I150/A5 then I300/A5, and 165 patients treated with I150 then I300. At randomization, mean home systolic blood pressure was similar in both groups: 152.7 (11.8) mm Hg in the I150/A5 group and 150.4 (10.1) mm Hg in the I150 group. At week 10, the adjusted mean difference in home systolic blood pressure between groups was -8.8 (1.1) mm Hg (P < 0.001). The percentage of controlled patients (mean home blood pressure <135 and 85 mm Hg) was nearly 2-fold higher in the I300/A5 group versus the I300 group (P < 0.001). Treatment-emergent adverse events were experienced by 10.5% of I300/A5-treated patients and 6.6% of I300-treated patients during the second 5-week period. Three serious adverse events were reported; 2 with monotherapy (1 with I150 and 1 with I300) and 1 with fixed-dose combination I300/A5. All patients affected by serious adverse events made a full recovery. These 10-week data from this patient population suggest a greater antihypertensive efficacy of the fixed-dose combination I300/A5 over I300 alone in lowering systolic blood pressure. Both treatments were well tolerated throughout the study. ClinicalTrials.gov identifier: NCT00957554.

Bobrie G ，I-ADD Study Investigators 《-》

I-COMBINE study: assessment of efficacy and safety profile of irbesartan/amlodipine fixed-dose combination therapy compared with amlodipine monotherapy in hypertensive patients uncontrolled with amlodipine 5 mg monotherapy: a multicenter, phase III, prosp

Hypertension guidelines recommend the use of 2 agents with synergistic action when >1 agent is needed to achieve blood pressure goals. Newer antihypertensive treatment combinations include fixed-dose combinations of an angiotensin receptor blocker and a calcium channel blocker. The I-COMBINE study aimed to determine whether the antihypertensive efficacy of the fixed-dose combination irbesartan 150 mg/amlodipine 5 mg (I150/A5) was superior to that of amlodipine 5 mg (A5) monotherapy in lowering home systolic blood pressure (HSBP) after 5 weeks' treatment. The I-COMBINE study was a 10-week, multicenter, Phase III, prospective, randomized, parallel-group, open-label with blinded-endpoint study. The main inclusion criterion was essential uncontrolled hypertension (SBP ≥145 mm Hg at office, after at least 4 weeks of A5 monotherapy administered once daily). Patients continued to receive A5 for 7 to 10 days and were randomized to either monotherapy with A5 for 5 weeks then amlodipine 10 mg (A10) for the next 5 weeks or to a fixed-dose combination therapy (I150/A5 then I150/A10). Safety profile was assessed by recording adverse events reported by patients or observed by the investigator. Following enrollment, 290 patients were randomized to treatment, and 287 (mean [SD] age, 57.3 [11.2] years; 48% male) were included in the intention-to-treat analysis: 144 patients treated with I150/A5 then I150/A10, and 143 patients treated with A5 then A10. At randomization, mean HSBP was similar in both groups: 148.5 (10.3) mm Hg in the I150/A5 group and 149.2 (9.7) mm Hg in the A5 group. At week 5, the adjusted mean difference in HSBP between groups was -6.2 (1.0) mm Hg (P < 0.001). The proportion of controlled patients (mean home blood pressure <135 and 85 mm Hg) was significantly higher in the I150/A5 group than in the A5 group (P < 0.001). Treatment-emergent adverse events were experienced by 13.8% of I150/A5-treated patients and 11.9% of A5-treated patients during the first 5-week period, and by 15.8% of I150/A10-treated patients and 17.0% of A10-treated patients during the second 5-week period. Two serious adverse events were reported with the fixed-dose combination; both patients recovered. Data from this adult population with essential hypertension suggest greater efficacy with the fixed-dose combination I150/A5 over A5 monotherapy in lowering SBP after 5 weeks. Both treatment regimens were well tolerated throughout the study. ClinicalTrials.gov identifier: NCT00956644.

Bobrie G ，I-COMBINE Study Investigators 《-》