Azilsartan medoxomil-CLD phase 3 study results in systolic blood pressure presented at ASH 2011

Takeda Global Research & Development Center, Inc. U.S., (TGRD U.S.) today announced results from three phase 3 studies of the investigational fixed-dose combination of azilsartan medoxomil plus chlorthalidone (CLD). In two phase 3 studies, azilsartan medoxomil combined in a fixed-dose with CLD lowered clinic systolic blood pressure (SBP) significantly more than the fixed-dose combination of olmesartan medoxomil plus hydrochlorothiazide (HCTZ). Another phase 3 study demonstrated that six fixed-dose combinations of azilsartan medoxomil plus CLD lowered mean trough (22-24 hours) SBP by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) significantly more than either azilsartan medoxomil or CLD alone.

Discovered by Takeda, azilsartan medoxomil is an angiotensin II receptor blocker (ARB) that lowers blood pressure by blocking the action of angiotensin II, a vasopressor hormone. Chlorthalidone is a long-acting diuretic used in the treatment of hypertension. All studies were presented at the American Society of Hypertension, Inc. (ASH) Twenty-Sixth Annual Scientific Meeting and Exposition (ASH 2011) in New York.  

"We were pleased with the results of the fixed-dose combination of azilsartan medoxomil plus chlorthalidone studies," said Domenic Sica, M.D., professor of internal medicine and nephrology at Virginia Commonwealth University Medical Center and lead investigator of the study. "If approved, the fixed-dose combination of azilsartan medoxomil plus chlorthalidone will be the first and only fixed-dose therapy in the U.S. that combines an ARB with the diuretic, chlorthalidone. This combination therapy can potentially provide a new treatment option for the millions of patients who are at risk of serious health consequences due to hypertension."

A New Drug Application, which was supported by five phase 3 clinical trials involving more than 5,000 patients with hypertension, was submitted to the Food and Drug Administration (FDA) for the fixed-dose combination of azilsartan medoxomil plus CLD in February 2011.

Fixed-Dose Combination of Azilsartan Medoxomil Plus CLD vs. Fixed-Dose Combination of Olmesartan Medoxomil and HCTZ (Forced titration) (LB-OR-03)

This phase 3, 12-week, randomized, double-blind study evaluated clinic SBP reductions of the fixed-dose combination of azilsartan medoxomil plus CLD and a fixed-dose combination of olmesartan medoxomil and HCTZ in 1,071 patients with hypertension.

In the two azilsartan medoxomil plus CLD fixed-dose combination groups, patients were force titrated from 20/12.5 mg and 40/12.5 mg to 40/12.5 mg and 80/12.5 mg at week 4, and to 40/25 mg and 80/25 mg at week 8, respectively. In the olmesartan medoxomil and HCTZ fixed-dose combination group, patients were force titrated from 20/12.5 mg to 40/12.5 mg at week 4 and to 40/25 mg at week 8.

Results, at week 12, showed that the two azilsartan medoxomil plus CLD fixed-dose combination groups reduced clinic SBP by 42.5 mm Hg and 44.0 mm Hg from baseline. The reductions were significantly greater than that of the fixed-dose combination of olmesartan medoxomil and HCTZ (37.1 mm Hg).  

Adverse events leading to temporary or permanent drug discontinuation occurred in 7.9 and 14.5 percent in the two groups of patients taking the fixed-dose combination of azilsartan medoxomil plus CLD and 7.1 percent of patients taking olmesartan medoxomil combined in a fixed-dose with HCTZ.

Fixed-Dose Combination of Azilsartan Medoxomil Plus CLD vs. Fixed-Dose Combination of Olmesartan Medoxomil and HCTZ (Poster #162)

This phase 3, eight-week, randomized, double-blind study evaluated clinic SBP reductions of the fixed-dose combination of azilsartan medoxomil plus CLD and a fixed-dose combination of olmesartan medoxomil and HCTZ in 1,085 patients with stage 2 hypertension.

In the two azilsartan medoxomil plus CLD fixed-dose combination groups, patients were titrated from 20/12.5 mg and 40/12.5 mg to 40/25 mg and 80/25 mg, respectively, at week four if they had not reached their target blood pressure goals. In the olmesartan medoxomil and HCTZ fixed-dose combination group, patients were titrated from 20/12.5 mg to 40/25 mg at week four if they had not reached their target blood pressure goals.

Results showed that the two azilsartan medoxomil plus CLD fixed-dose combination groups reduced clinic SBP by 37.6 and 38.2 mm Hg from baseline at week eight. The reductions were significantly greater than that of the fixed-dose combination of olmesartan medoxomil and HCTZ (31.5 mm Hg). Fewer patients in the azilsartan medoxomil fixed-dose combination groups were titrated at week four to a higher dose than in the olmesartan medoxomil and HCTZ fixed-dose combination group.

Adverse events leading to temporary or permanent drug discontinuation occurred in 6.2 percent and 9.5 percent in the two groups of patients taking the fixed-dose combination of azilsartan medoxomil plus CLD, and 3.1 percent of patients taking olmesartan medoxomil combined in a fixed-dose with HCTZ.

Fixed-Dose Combination of Azilsartan Medoxomil Plus CLD vs. Azilsartan Medoxomil and CLD Monotherapies (Poster #182)

This phase 3, eight-week, randomized, double-blind, factorial study evaluated various fixed-dose combinations of azilsartan medoxomil plus CLD in 1,714 patients with stage 2 hypertension. The change in trough (22-24 hours) SBP by 24-hour ABPM from baseline to week eight was examined as a primary endpoint among six different fixed-dose combinations of azilsartan medoxomil 20 mg/day, 40 mg/day and 80 mg/day plus CLD 12.5 and 25 mg/day.

The study demonstrated the six fixed-dose combinations of azilsartan medoxomil plus CLD lowered trough SBP by a range of 22.9 mm Hg to 29.8 mm Hg from baseline at week eight. All reductions were significantly greater than those of azilsartan medoxomil monotherapies (12.1 mm Hg to 15.1 mm Hg) or CLD monotherapies (12.7 mm Hg to 15.9 mm Hg).

Adverse events leading to temporary or permanent drug discontinuation occurred more frequently in the azilsartan medoxomil plus CLD combination groups (3.4-14.3 percent) compared to the monotherapy groups [azilsartan medoxomil monotherapy (1.9-4.3 percent); CLD monotherapy (1.9-3.8 percent)]. Increases in serum creatinine occurred more frequently with the fixed-dose combinations of azilsartan medoxomil plus CLD relative to either monotherapy agent, and were dose-dependent.  

SOURCE Takeda Global Research & Development Center, Inc. U.S.