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New Data Demonstrates Investigational Triple Antihypertensive Combination Therapy Produces Superior Blood Pressure Reductions Compared to Corresponding Dual Treatments

Sunday, May 2, 2010 General News J E 4
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PARSIPPANY, N.J., May 1 Results of a new study found that the investigational triple combination therapy of olmesartan medoxomil (OM), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) demonstrated significantly greater mean reductions at week 12 in blood pressure (37.1/21.8 mm Hg versus 27.5 to 30.0/15.1-18.0 mm Hg LS Mean Reductions, P< 0.0001), as compared to corresponding dual combination therapy (dual components).(1)

The study, presented at the American Society of Hypertension (ASH) annual meeting in New York, also found that at week 12, a significantly greater percentage of patients treated with the investigational triple combination therapy (OM/AML/HCTZ 40/10/25 mg) reached blood pressure goal (<140/90 mm Hg or <130/80 mm Hg for patients with diabetes, chronic renal disease, or chronic cardiovascular disease), as compared to corresponding dual components (64.3 percent versus 34.9 to 46.6 percent; P<0.0001, all comparisons).(1) The triple therapy was well tolerated with most reported adverse events defined as mild or moderate.(2)

"Many patients with hypertension fail to reach recommended blood pressure targets even when taking more than one therapy," said Suzanne Oparil, MD, Professor of Medicine and Physiology and Biophysics at the University of Alabama School of Medicine. "This study demonstrated that treating patients with a triple combination therapy regimen, each component which has a different mechanism of action, is more effective at lowering blood pressure than the dual combination of any two individual components and was well tolerated among the patients studied."

The TRINITY study, (Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study) is a Phase 3, multicenter, randomized, parallel-group study, which included 2,492 patients with moderate to severe hypertension. The study consisted of a double-blind 12 week treatment period, followed by a 40 week open-label period.(1) The 12 week results have been disclosed today. The study found that blood pressure-lowering and percentage of patients reaching the current recommended blood pressure target was greater with the triple combination therapy versus corresponding dual combination therapy regardless of gender, age, race, and hypertension severity (P<0.0001).(1) Ambulatory blood pressure was measured in a subset of 380 patients at baseline and week 12. Twenty-four hour ambulatory blood pressure monitoring revealed greater effects with the triple combination therapy versus corresponding dual combination therapy (P<0.0001).(3) After 12 weeks of treatment, the group receiving triple combination (OM/AML/HCTZ 40/10/25 mg, n=100) achieved a mean 24-hour ambulatory blood pressure of 117/69 mm Hg (baseline 24-hour blood pressure, 147/87 mm Hg) compared to those patients taking dual combination therapy for which ambulatory blood pressure ranged from 126/74 mm Hg to 128/77 mm Hg (baseline 24-hour blood pressure 147-149/89 mm Hg), P<0.0001, all comparisons.(3)

Age and Gender

A pre-specified subgroup analysis showed that at week 12, among 1,304 male and 1,154 female patients, reductions in blood pressure were significantly greater (P<0.0001) for both genders with olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide 40/10/25 mg (male, n=316; female, n=298) than with corresponding dual components.(4) Similarly, regardless of whether patients were younger than (n=1,989) or older than 65 years (n=469), olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide 40/10/25 mg resulted in significantly greater reductions in diastolic blood pressure (P less than or equal to 0.002) and systolic blood pressure (P<0.0001).(4) The incidence of treatment-emergent adverse events was comparable between groups and most adverse events were mild or moderate in severity.(4)

Black and Non-black

A pre-specified subgroup analysis of the study examined efficacy and safety in black (n=740) and non-black patients (n=1,718). Statistically significant reductions in diastolic and systolic blood pressure from baseline to week 12 (P<0.0001 for both) were observed in both race subgroups for all four study treatment groups.(5) Olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide 40/10/25 mg resulted in significantly greater mean reductions in diastolic blood pressure in both black (21.5 versus 15.1 to 18.1 mm Hg for dual components) and non-black groups (21.5 versus 14.7 to 17.7 mm Hg for dual components) and in systolic blood pressure (P<0.0001 for black and non-black groups).(5) Mean baseline blood pressure for OM/AML/HCTZ 40/10/25 mg in black group was 168.4/102.6 mm Hg; non-black group was 167.8/100.2 mm Hg. Mean baseline blood pressure for corresponding dual components in black group was 168.0-170.2/102-103.5 mm Hg; non-black group was 168.0-169.0/100-100.7 mm Hg.(5) Olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide resulted in a significantly greater percentage of patients reaching blood pressure goal of <140/90 mm Hg or <130/80 mm Hg for patients with diabetes, chronic renal disease, or chronic cardiovascular disease (P less than or equal to 0.0009) at week 12, with 62 percent of black patients reaching blood pressure goal with the triple combination therapy compared to 37 to 44 percent for the dual components.(5) For non-black patients, the percentage reaching blood pressure goal was significantly greater at 66 percent for olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide as compared to 34 to 48 percent for the dual components (P<0.0001). The incidence of treatment-emergent adverse events was comparable between groups and most adverse events were mild or moderate.(5)

Hypertension Severity

An additional pre-specified sub-analysis evaluated blood pressure efficacy according to hypertension severity. The mild to moderate hypertension group included patients with systolic blood pressure from 140 to <180 mm Hg and diastolic blood pressure from 90 to <110 mm Hg (n=1,776), and the severe hypertension group included patients with systolic blood pressure greater than or equal to 180 mm Hg or diastolic blood pressure greater than or equal to 110 mm Hg (n=624). Due to patient eligibility, based on different visits than those that determined baseline blood pressure as well as the known variability of blood pressure over time, 11 percent of the total population had mild hypertension and 86.5 percent had moderate to severe (stage 2) hypertension.(6)

Olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide 40/10/25 mg resulted in greater mean reductions in diastolic blood pressure and systolic blood pressure (P less than or equal to 0.0013 and P<0.0001, respectively) compared to the corresponding dual component groups regardless of hypertension severity. The incidence of treatment-emergent adverse events (TEAEs), the majority of which were mild or moderate, was comparable between hypertension severity subgroups.(6)

Study Design

The study consisted of a double-blind 12 week treatment period, followed by a 40 week open-label period. The 12 week results have been disclosed today at ASH 2010.

In this first trial to investigate the efficacy of the triple combination antihypertensive therapy of olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide 40/10/25 mg, patients received one of three dual combination therapies or placebo (n=36) for the first two weeks of the study: olmesartan medoxomil (40 mg)/ amlodipine besylate (10 mg), olmesartan medoxomil (40 mg)/ hydrochlorothiazide (25 mg) or amlodipine besylate (10 mg) and hydrochlorothiazide (25 mg). After the first two weeks, until week four, the 36 patients on placebo were switched to one of the dual combination therapies. At four weeks, the triple combination therapy of olmesartan medoxomil (40 mg) / amlodipine besylate (10 mg) / hydrochlorothiazide (25 mg) was started in a subset of patients (n=627) from each of the three dual combination groups and continued for 12 weeks followed by a 40 week open-label treatment period.(1)

Safety & Tolerability

Across all groups, drug-related treatment adverse events were reported in 25.4 percent of patients. Most TEAEs and drug-related TEAEs were mild or moderate in severity. More discontinuations due to AEs occurred in the olmesartan medoxomil/ amlodipine besylate/ hydrochlorothiazide (4.0 percent) versus the dual combination therapy groups (1.0-2.1 percent). Events leading to discontinuation included dizziness, hypotension, syncope, and hence the higher discontinuation rate was attributed to the more pronounced pharmacodynamic effect of the triple combination.(2)

In addition, discontinuations for patients on triple combination therapy also included subjects who experienced an adverse event on earlier treatment (i.e. placebo or dual), prior to initiation of the triple combination regimen.(2)

About The Triple Combination Therapy

A fixed-dose, single pill of olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide is currently under review for approval with the US Food and Drug Administration (FDA) for the treatment of hypertension.

About Daiichi Sankyo

In keeping with its vision of becoming a "Global Pharma Innovator," the Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address the diversified, unmet medical needs of customers in both developed and emerging markets. While maintaining its portfolio of marketed pharmaceuticals for hypertension, hyperlipidemia, and bacterial infections, the Group is engaged in the development of treatments for thrombotic disorders and focused on the discovery of novel oncology and cardiovascular-metabolic therapies. Furthermore, the Daiichi Sankyo Group has created a "Hybrid Business Model," which will respond to market and customer diversity and optimize growth opportunities across the value chain. For more information, please visit www.daiichisankyo.com.

Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is the U.S. subsidiary of Daiichi Sankyo Company, Ltd. For more information on Daiichi Sankyo, Inc., please visit www.dsi.com.

(1) CS-8635 Abstract: Efficacy and Safety of Combination Olmesartan Medoxomil (OM)+Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ) in Patients With Hypertension: The Trinity Study. (2) CS-8635 Abstract: Safety and Tolerability of Combination Olmesartan Medoxomil (OM)+Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ) in Patients With Hypertension. (3) CS-8635 Abstract: 24-Hour Efficacy and Safety of Full-dose, Triple-Combination Therapy With Olmesartan, Amlodipine Besylate, And Hydrochlorothiazide. (4) CS-8635 Abstract: Efficacy and Safety of Combination Olmesartan Medoxomil (OM)+Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ) in Patients With Hypertension: Analysis by Age and Gender. (5) CS-8635 Abstract: Efficacy and Safety of Combination Olmesartan Medoxomil (OM)+Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ). The Trinity Study: A Subgroup Analysis by Race. (6) CS-8635 Abstract: Efficacy and Safety of Combination Olmesartan Medoxomil (OM)+Amlodipine Besylate (AML)+Hydrochlorothiazide (HCTZ) Based on Severity of Hypertension: The Trinity Study.

SOURCE Daiichi Sankyo, Inc.
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