A randomized, double-blind, placebo-controlled trial to evaluate the safety and effectiveness of intracoronary application of a novel bioabsorbable cardiac matrix for the prevention of ventricular remodeling after large ST-segment elevation myocardial infarction: Rationale and design of the PRESERVATION I trial.

Postinfarction left ventricular (LV) remodeling can result in chronic heart failure and functional impairment. Although pharmacological strategies for established heart failure can be beneficial, preventing remodeling remains a challenge. Injectable bioabsorbable alginate or "bioabsorbable cardiac matrix" (BCM), composed of an aqueous mixture of sodium alginate and calcium gluconate, is a sterile colorless liquid that is a polysaccharide polymer produced from brown seaweed. When exposed to excess ionized calcium present in infarcted myocardium, BCM assembles to form a flexible gel, structurally resembling extracellular matrix, which provides temporary structural support to the infarct zone through and beyond the time needed for mature fibrotic tissue to develop. The PRESERVATION I trial is an early phase randomized, double-blind, placebo-controlled trial comparing intracoronary application of 4 mL of BCM with saline control in patients who develop large infarctions after successful reperfusion of large ST-segment elevation myocardial infarction (MI). Subjects will be randomized 2:1 to either BCM or saline control and will have the study device deployed through an intracoronary microcatheter in the infarct-related artery 2 to 5 days after index ST-segment elevation MI treated with successful primary or rescue percutaneous coronary intervention. The primary effectiveness end point is the absolute change in LV diastolic volume index as measured by 3-dimensional echocardiography from baseline to 6 months after BCM deployment. Secondary effectiveness end points include clinical outcomes, patient-reported quality of life, additional echocardiographic measures, and functional status measures. In summary, the PRESERVATION I trial is a randomized double-blind trial evaluating the effectiveness and safety of the novel device BCM in preventing LV remodeling patients who have large MIs despite undergoing successful primary or rescue percutaneous coronary intervention.

Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double-blind, parallel-group TRINITY study.

BACKGROUND: Patients with hypertension and cardiovascular disease (CVD), diabetes, or chronic kidney disease (CKD) usually require two or more antihypertensive agents to achieve blood pressure (BP) goals. METHODS: The efficacy/safety of olmesartan (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg versus the component dual-combinations (OM 40/AML 10 mg, OM 40/HCTZ 25 mg, and AML 10/HCTZ 25 mg) was evaluated in participants with diabetes, CKD, or chronic CVD in the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY). The primary efficacy end point was least squares (LS) mean reduction from baseline in seated diastolic BP (SeDBP) at week 12. Secondary end points included LS mean reduction in SeSBP and proportion of participants achieving BP goal (<130/80 mm Hg) at week 12 (double-blind randomized period), and LS mean reduction in SeBP and BP goal achievement at week 52/early termination (open-label period). RESULTS: At week 12, OM 40/AML 10/HCTZ 25 mg resulted in significantly greater SeBP reductions in participants with diabetes (-37.9/22.0 mm Hg vs -28.0/17.6 mm Hg for OM 40/AML 10 mg, -26.4/14.7 mm Hg for OM 40/HCTZ 25 mg, and -27.6/14.8 mm Hg for AML 10/HCTZ 25 mg), CKD (-44.3/25.5 mm Hg vs -39.5/23.8 mm Hg for OM 40/AML 10 mg, -25.3/17.0 mm Hg for OM 40/HCTZ 25 mg, and -33.4/20.6 mm Hg for AML 10/HCTZ 25 mg), and chronic CVD (-37.8/20.6 mm Hg vs -31.7/18.2 mm Hg for OM 40/AML 10 mg, -30.9/17.1 mm Hg for OM 40/HCTZ 25 mg, and -27.5/16.1 mm Hg for AML 10/HCTZ 25 mg) (P<0.05 for all subgroups vs dual-component treatments). BP goal achievement was greater for participants receiving triple-combination treatment compared with the dual-combination treatments, and was achieved in 41.1%, 55.0%, and 38.9% of participants with diabetes, CKD, and chronic CVD on OM 40/AML 10/HCTZ 25 mg, respectively. At week 52, there was sustained BP lowering with the OM/AML/HCTZ regimen. Overall, the triple combination was well tolerated. CONCLUSIONS: In patients with diabetes, CKD, or chronic CVD, short-term (12 weeks) and long-term treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated, lowered BP more effectively, and enabled more participants to reach BP goal than the corresponding 2-component regimens. TRIAL IDENTIFICATION NUMBER: NCT00649389.

Pharmacokinetics of amlodipine and olmesartan after administration of amlodipine besylate and olmesartan medoxomil in separate dosage forms and as a fixed-dose combination.

The pharmacokinetics of amlodipine and olmesartan in healthy volunteers after coadministration of amlodipine besylate and olmesartan medoxomil concomitantly as separate dosage forms and together in a fixed-dose combination tablet were characterized in 5 phase I, randomized, crossover studies. The mean steady-state pharmacokinetics of amlodipine and olmesartan were similar when olmesartan medoxomil 40 mg/day and amlodipine 10 mg/day were administered separately or concomitantly for 10 days. The total and maximum exposure to amlodipine and olmesartan after administration of fixed-dose combination amlodipine/olmesartan medoxomil 10 mg/40 mg was bioequivalent to amlodipine 10 mg plus olmesartan medoxomil 40 mg. The ratio of least squares mean and 90% confidence intervals for the area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of amlodipine and olmesartan fell within the prespecified range for bioequivalence (80.0% - 125.0%). The area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of both drugs also met the prespecified criterion for bioequivalence when the fixed-dose combination tablet was taken 30 minutes after a high-fat breakfast. Total exposure to amlodipine and olmesartan was dose-proportional after administration of olmesartan medoxomil 10 mg to 40 mg in the fixed-dose combination formulation with amlodipine 5 mg to 10 mg. From a pharmacokinetic perspective, the 2 drugs are well suited to coadministration in a fixed-dose combination.

The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study.

BACKGROUND: Hypertension guidelines recommend the use of 2 agents having complementary mechanisms of action when >1 agent is needed to achieve blood pressure (BP) goals. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of combinations of olmesartan medoxomil (OM) and amlodipine besylate with those of the component monotherapies in patients with mild to severe hypertension. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, factorial study. Patients who were naive to antihypertensive therapy or who underwent a washout of previous antihypertensive therapy for up to 2 weeks and had a seated diastolic BP (SeDBP) of 95 to 120 mm Hg were randomized to receive 1 of the following for 8 weeks: OM 10, 20, or 40 mg; amlodipine (AML) 5 or 10 mg; each possible combination of OM and AML; or placebo. The primary end point was the change from baseline in SeDBP at week 8, with secondary end points including the change in seated systolic blood pressure (SeSBP), the proportion of patients reaching the BP goal (<140/90 mm Hg; <130/80 mm Hg for patients with diabetes), and the proportions of the intention-to-treat population reaching BP thresholds of <120/80, <130/80, <130/85, and <140/90 mm Hg. Safety and tolerability were also evaluated, with a particular focus on the incidence and severity of edema. RESULTS: Of the 1940 randomized patients, 54.3% were male. The mean age of the study population was 54.0 years and 19.8% were aged >or=65 years. The mean baseline BP was 164/102 mm Hg, and 79.3% of patients had stage 2 hypertension. Combination therapy with OM and AML was associated with dose-dependent reductions in SeDBP (from -13.8 mm Hg with OM/AML 10/5 mg to -19.0 mm Hg with OM/AML 40/10 mg) and SeSBP (from -23.6 mm Hg with OM/AML 20/5 mg to -30.1 mm Hg with OM/AML 40/10 mg) that were significantly greater than the reductions with the corresponding component monotherapies (P<0.001). At week 8, the number of patients achieving the BP goal ranged from 57 of 163 (35.0%) to 84 of 158 (53.2%) in the combination-therapy groups, from 32 of 160 (20.0%) to 58 of 160 (36.3%) in the OM monotherapy groups, and from 34 of 161 (21.1%) to 53 of 163 (32.5%) in the AML monotherapy groups (P<0.005, combination therapies vs component monotherapies), compared with 14 of 160 (8.8%) in the placebo group. Achievement of the BP thresholds was highest in the combination-therapy groups, with 56.3% and 54.0% of patients achieving a BP <140/90 mm Hg with OM/AML 20/10 and 40/10 mg, respectively. Combination therapy was generally well tolerated, and no unexpected safety concerns emerged in the course of the study. The most common adverse events were edema (ranging from 9.9% [OM 20 mg] to 36.8% [AML 10 mg], compared with 12.3% with placebo) and headache (ranging from 2.5% [OM/AML 10/5 mg] to 8.7% [OM 20 mg], compared with 14.2% with placebo). CONCLUSION: The combination of OM and AML was effective and well tolerated in this adult population with hypertension.

Bioabsorbable Intracoronary Matrix for Prevention of Ventricular Remodeling After Myocardial Infarction.

BACKGROUND: Bioabsorbable cardiac matrix (BCM) is a novel device that attenuates adverse left ventricular (LV) remodeling after large myocardial infarctions in experimental models. OBJECTIVES: This study aimed to analyze whether BCM, compared with saline control, would result in less LV dilation and fewer adverse clinical events between baseline and 6 months. METHODS: In an international, randomized, double-blind, controlled trial, 303 subjects with large areas of infarction despite successful primary percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) were randomized 2:1 to BCM or saline injected into the infarct-related artery 2 to 5 days after primary PCI. The primary outcome was mean change from baseline in LV end-diastolic volume index (LVEDVI) at 6 months. Secondary outcomes included change in Kansas City Cardiomyopathy Questionnaire score, 6-minute walk time, and New York Heart Association functional class at 6 months. The primary safety endpoint was a composite of cardiovascular death, recurrent MI, target-vessel revascularization, stent thrombosis, significant arrhythmia requiring therapy, or myocardial rupture through 6 months. RESULTS: In total, 201 subjects were assigned to BCM and 102 to saline control. There was no significant difference in change in LVEDVI from baseline to 6 months between the groups (mean change ± SD: BCM 14.1 ± 28.9 ml/m(2) vs. saline 11.7 ± 26.9 ml/m(2); p = 0.49). There was also no significant difference in the secondary endpoints. The rates of the primary safety outcome were similar between the 2 groups (BCM 11.6% vs. saline 9.1%; p = 0.37). CONCLUSIONS: Intracoronary deployment of BCM 2 to 5 days after successful reperfusion in subjects with large myocardial infarction did not reduce adverse LV remodeling or cardiac clinical events at 6 months. (IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction [PRESERVATION I]; NCT01226563).

Combined olmesartan, amlodipine, and hydrochlorothiazide therapy in randomized patients with hypertension: a subgroup analysis of the TRINITY study by age.

BACKGROUND: Hypertension is often inadequately controlled in older people. OBJECTIVE: This prespecified subgroup analysis assessed the efficacy and safety of an olmesartan medoxomil (OM) 40 mg/amlodipine besylate (AML) 10 mg/hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the 3 components as dual-combination treatments in participants with hypertension who were <65 and ≥ 65 years of age. Within the ≥ 65 years of age subgroup, efficacy and safety were also summarized for participants ≥ 75 years of age. STUDY DESIGN: 12-week, multicenter, double-blind, randomized, parallel-group study. SETTING: 317 ambulatory care sites in the US and Puerto Rico. PARTICIPANTS: Individuals ≥ 18 years of age with mean seated blood pressure (SeBP) ≥ 140/100 or ≥ 160/90 mmHg off antihypertensive medication on 2 consecutive clinic visits with no recent history of significant cerebrovascular disease, coronary artery disease, heart failure (New York Heart Association class III or IV), severe renal insufficiency, or uncontrolled diabetes (HbA1c >9 %). INTERVENTION: Participants were randomized, stratified by age, diabetes status, and race to one of four treatment assignments: OM 40/AML 10/HCTZ 25 mg, OM 40/AML 10 mg, OM 40/HCTZ 25 mg, or AML 10/HCTZ 25 mg. MAIN OUTCOME MEASURE: Least squares (LS) mean change from baseline in seated diastolic blood pressure (SeDBP) at week 12 (last observation carried forward) in each age subgroup (prespecified analysis). RESULTS: Of the 2492 randomized participants in the study (total cohort), 2021 (81.1 %) were <65 and 471 (18.9 %) were ≥ 65 years of age, including 79 (3.2 %) who were ≥ 75 years of age. OM 40/AML 10/HCTZ 25 mg triple-combination treatment resulted in a significantly greater reduction in LS mean SeDBP at week 12 than dual-combination component treatments in participants in both cohorts: <65 years (21.0 vs. 14.2-17.2 mmHg; p < 0.0001) and ≥ 65 years (23.7 vs. 17.3-20.0 mmHg; p ≤ 0.002). Similarly, triple-combination treatment resulted in a greater reduction in LS mean seated systolic blood pressure (SeSBP) at week 12 than dual-combination component treatments: <65 years (38.2 vs. 28.3-31.4 mmHg; p < 0.0001) and ≥ 65 years (39.2 vs. 29.3-31.1 mmHg; p < 0.0001). Triple-combination treatment was more effective than dual-combination treatments in enabling participants to reach SeBP goal (<140/90 mmHg [<130/80 mmHg in participants with diabetes, chronic kidney disease, or chronic cardiovascular disease]) in both age subgroups (<65 years: 65 vs. 34-50 %, respectively, p < 0.0001 and ≥ 65 years: 63 vs. 32-39 %; p ≤ 0.0004). All 4 treatments were safe and well tolerated with low discontinuation rates in both age subgroups. There were no clinically relevant differences in the incidence of treatment-emergent adverse events between participants <65 and ≥ 65 years of age receiving triple-combination treatment. CONCLUSION: Triple-combination treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated and more effective in lowering BP than the component dual-combination treatments in elderly and non-elderly subgroups.

Olmesartan/amlodipine/hydrochlorothiazide in obese participants with hypertension: a TRINITY subanalysis.

The objective of this prespecified TRINITY study subgroup analysis was to assess the efficacy and safety of triple-combination treatment with olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg vs the component dual-combination treatments in obese (body mass index [BMI] ≥30 kg/m(2) ) and nonobese (BMI <30 kg/m(2) ) hypertensive participants. The double-blind treatment period primary end point was the least-squares (LS) mean reduction in seated diastolic BP (SeDBP) at week 12 (end of the double-blind period). Of the 2492 randomized participants, 1555 (62.4%) had BMI ≥30 kg/m(2) . Irrespective of BMI, triple-combination treatment resulted in greater LS mean reductions in seated BP (SeBP) (≥30 kg/m(2) , 6.7-10.5/4.5-7.3 mm Hg; <30 kg/m(2) , 5.1-8.6/2.5-6.0 mm Hg [P<.005] vs dual-combination treatments for both subgroups) at week 12. Furthermore, triple-combination treatment enabled a greater proportion of participants to reach BP goal vs the dual-combination treatments (≥30 kg/m(2) , 62% vs 31%-46% [P<.0001]; <30 kg/m(2) , 69% vs 41%-55% [P<.005]) at week 12. SeBP reduction and goal attainment (≥30 kg/m(2) , 63%; <30 kg/m(2) , 67%) was maintained through week 52/early termination. Triple-combination treatment was well tolerated in both BMI subgroups.

The TRINITY Study: distribution of systolic blood pressure reductions.

BACKGROUND: Elevated systolic blood pressure is more difficult to control than elevated diastolic blood pressure. The objective of this prespecified analysis of the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) was to compare the efficacy of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment with the component dual-combination treatments in reducing elevated seated systolic blood pressure (SeSBP). METHODS: The 12-week TRINITY study randomized participants to either one of the three component dual-combination treatments (OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg) or the triple-combination treatment. The primary outcome of this analysis was the categorical distribution of SeSBP reductions at week 12 from baseline with OM 40 mg/AML 10 mg/HCTZ 25 mg versus the dual-combination treatments. RESULTS: SeSBP reductions >50 mmHg were seen in 24.4% of participants receiving triple-combination treatment versus 8.1%-15.8% receiving dual-combination treatment. More participants receiving triple-combination treatment achieved the SeSBP target of <140 mmHg (73.6% versus 51.3%-58.8%; P < 0.001) and the seated blood pressure target of <140/90 mmHg (69.9% versus 41.1%-53.4%; P < 0.001). Prevalence and severity of adverse events were similar in all treatment groups. CONCLUSION: Treatment with OM 40 mg/AML 10 mg/HCTZ 25 mg was well tolerated and more effective in reducing SeSBP than the dual-combination treatments.

Model-Supported Development of CS-8635: A Fixed-Dose Combination of Olmesartan, Amlodipine, and Hydrochlorothiazide.

CS-8635, a fixed-dose triple combination of olmesartan, amlodipine, and hydrochlorothiazide, was developed to address the growing need for additional blood pressure (BP) reduction in patients not controlled with dual-combination therapies. Prior to Phase III, modeling and simulation (M&S) was conducted to estimate the additional BP lowering effect of CS-8635 compared to the respective dual combinations. The Phase III study evaluated CS-8635 BP lowering effects only at the highest dose strength among the five dose strengths to be developed. Post-trial M&S was performed using an integrated dataset from three Phase III programs; CS-8635 plus two prior dual combinations. M&S robustly estimated and described the BP lowering effects of CS-8635 evaluated in a clinical setting. Furthermore, M&S evaluated BP lowering effects of the additional four dose strengths not studied. In summary, M&S aided the development of the clinical study and full characterization of the BP lowering effects of CS-8635 across intermediate doses.

Long-term efficacy and safety of triple-combination therapy with olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide for hypertension.

J Clin Hypertens (Greenwich). 2012;14:149-157. ©2012 Wiley Periodicals, Inc. Most patients with hypertension require combination therapy in order to achieve blood pressure (BP) goals. This 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide (OM/AML/HCTZ) in 2112 participants with moderate to severe hypertension. Following 2 weeks of initial treatment with OM 40/AML 5/HCTZ 12.5 mg, participants not achieving BP goal were titrated to OM 40/AML 5/HCTZ 25 mg or OM 40/AML 10/HCTZ 12.5 mg on a randomized basis. At week 16, participants who did not achieve BP goal were further titrated to OM 40/AML 10/HCTZ 25 mg. At the end of the study, 44.5% to 79.8% of participants reached BP goal and the mean BP decreased from 168.6/100.7 mm Hg (baseline BP at randomization) to 125.0 to 136.8 mm Hg/77.8 to 82.5 mm Hg, depending on treatment. Long-term treatment with OM/AML/HCTZ was well tolerated and effective with no new safety concerns.

Efficacy and safety of triple-combination therapy with olmesartan, amlodipine, and hydrochlorothiazide in study participants with hypertension and diabetes: a subpopulation analysis of the TRINITY study.

BACKGROUND: Most patients with hypertension and diabetes require two or more antihypertensive agents to achieve the recommended blood pressure (BP) goal of <130/80 mm Hg. This prespecified subgroup analysis from the TRIple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in HyperteNsIve PatienTs StudY assessed the efficacy and safety of triple-combination treatment (olmesartan medoxomil 40/amlodipine besylate 10/hydrochlorothiazide 25 mg) versus the component dual-combination treatments according to diabetes status (diabetes; non-diabetes). METHODS: Participants received dual-combination treatment for 4 weeks or placebo for 2 weeks. Participants receiving placebo switched to dual-combination treatment from week 2 to week 4. At week 4, participants switched to triple-combination treatment or continued on dual-combination treatment until week 12. RESULTS: The prespecified changes in BP from baseline for the diabetes subgroup receiving triple-combination treatment were greater than the respective dual-combination treatments (P ≤ .0013). Also, more participants with diabetes receiving triple-combination treatment reached BP goal (<130/80 mm Hg) versus those receiving dual-combination treatments (P ≤ .0092). In a post hoc analysis, significantly greater proportions of study participants with diabetes achieved BP targets with triple-combination treatment compared with each dual-combination treatment. Most treatment-emergent adverse events were mild to moderate in severity. CONCLUSIONS: In participants with hypertension and diabetes, triple-combination treatment led to greater BP reductions and enabled greater proportions of participants to reach BP goal versus the dual-combination treatments. Triple-combination treatment was well tolerated in both diabetes and non-diabetes subgroups.

Triple-Combination therapy with olmesartan, amlodipine, and hydrochlorothiazide in black and non-black study participants with hypertension: the TRINITY randomized, double-blind, 12-week, parallel-group study.

BACKGROUND: Although awareness of hypertension in Black patients has increased, blood pressure (BP) is frequently inadequately controlled. OBJECTIVE: This prespecified subgroup analysis of the TRINITY study evaluated the efficacy and safety of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the component dual-combination treatments in Black and non-Black study participants. STUDY DESIGN: TRINITY was a 12-week, randomized, double-blind, parallel-group evaluation. The first patient was enrolled in May 2008 and the last patient completed the study in February 2009. The study consisted of a 3-week washout period for participants receiving antihypertensive therapy and a 12-week double-blind treatment period. For the treatment phase, all study participants were stratified by age, race, and diabetes mellitus status and randomized to a treatment sequence that led to their final treatment assignment, which they received from weeks 4 to 12 (OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg). In the first 2 weeks of the double-blind treatment period, all participants received either dual-combination treatment or placebo. Participants assigned to dual-combination treatment continued treatment until week 4, and participants receiving placebo were switched at week 2 to receive one of the dual-combination treatments until week 4. At week 4, participants either continued dual-combination treatment or randomly received triple-combination treatment until week 12. SETTING: 317 clinical sites in the USA and Puerto Rico were included in the study. PATIENTS: Study participants eligible for randomization (N = 2492) were ≥18 years of age with mean seated blood pressure (SeBP) ≥140/100 mmHg or ≥160/90 mmHg (off antihypertensive medication). INTERVENTION: The intervention was with dual- or triple-combination antihypertensive treatment: OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg. MAIN OUTCOME MEASURE: The primary efficacy variable was the change in least squares (LS) mean seated diastolic BP (SeDBP) from baseline to week 12. Secondary efficacy variables included the LS mean change in seated systolic BP (SeSBP), percentage of study participants reaching BP goal, and safety parameters. RESULTS: In both Black and non-Black participants, triple-combination treatment resulted in significant and similar mean reductions in SeDBP and SeSBP (p ≤ 0.0001 vs each dual-combination treatment) with a greater proportion of participants reaching BP goal compared with dual-combination treatments, regardless of race. Most treatment-emergent adverse events were mild or moderate in severity and no new safety concerns were identified. CONCLUSION: Triple-combination treatment provided greater BP reductions than dual-combination treatments regardless of race. CLINICAL TRIAL REGISTRATION: Registered at ClinicalTrials.gov as NCT00649389.

Pharmacokinetics of olmesartan medoxomil in pediatric patients with hypertension.

BACKGROUND: The prevalence and importance of hypertension in younger patients is becoming increasingly recognized; however, only a limited number of clinical trials have been conducted in the pediatric population. OBJECTIVE: The aim of this study was to characterize the pharmacokinetics and short-term safety of olmesartan medoxomil in children and adolescents with hypertension. METHODS: An open-label, multicenter, single-dose study was conducted in children and adolescents aged 12 months-16 years who were receiving treatment for hypertension or, if not currently treated for hypertension, had either a systolic blood pressure (SBP) or diastolic blood pressure (DBP).≥95th percentile, or SBP or DBP ≥90th percentile if diabetic or with a family history of hypertension. Patients were stratified by age: 12-23 months (Group 1; none enrolled), 2-5 years (Group 2; n = 4), 6-12 years (Group 3; n = 10), and 13-16 years (Group 4; n = 10). All patients received a single oral dose of olmesartan medoxomil based on the individual's age and bodyweight. Patients aged <6 years received an oral suspension of olmesartan medoxomil at a dose of 0.3 mg/kg of bodyweight (not to exceed 20 mg), those aged ≥6 years who weighed ≥35 kg received olmesartan medoxomil 40 mg tablets, and those who weighed <35 kg received olmesartan medoxomil 20 mg tablets. RESULTS: In Groups 2, 3, and 4, the weight-adjusted apparent total body clearance (CL/F) of olmesartan medoxomil was 0.100 ± 0.034, 0.062 ± 0.020, and 0.072 ± 0.022 L/h/kg, respectively, and the weight-adjusted apparent volume of distribution (Vd/F) was 0.32 ± 0.16, 0.33 ± 0.14, and 0.49 ± 0.23 L/kg, respectively. CL/F and Vd/F in Groups 3 and 4 were not significantly different. Statistical comparisons between Groups 3 or 4 and Group 2 were not performed due to the small sample size of Group 2 (n = 4). Plasma elimination half-life and time to maximum plasma concentration were similar across the three groups. In Groups 3 and 4, considerable interindividual variability was seen in maximum plasma concentration (C(max)), area under the curve (AUC) from time zero to the last measurable concentration, and apparent clearance, with AUC and C(max) approximately 30% greater in Group 3. Four of 24 (16.7%) patients experienced treatment-emergent adverse events that were all mild in severity and considered not drug-related. No deaths, serious adverse events, or discontinuations due to adverse events occurred in the study. CONCLUSIONS: Olmesartan medoxomil was well tolerated and demonstrated a pharmacokinetic profile in pediatric patients similar to that of adults when adjusted for body size. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00151814

24-hour efficacy and safety of Triple-Combination Therapy With Olmesartan, Amlodipine, and Hydrochlorothiazide: the TRINITY ambulatory blood pressure substudy.

This 12-week, multicenter, randomized, double-blinded, 4-arm study in 440 patients with moderate to severe hypertension compared ambulatory blood pressure (ABP) responses with a triple-combination regimen (olmesartan medoxomil [OM] 40 mg, amlodipine besylate [AML] 10 mg, and hydrochlorothiazide [HCTZ] 25 mg) and its component dual-combination regimens at similar doses. At week 12, the triple combination resulted in a greater reduction in mean 24-hour systolic and diastolic blood pressure (-30.3/-18.0 mm Hg) compared with the 3 dual-combination regimens (OM 40 mg/AML 10 mg: -23.5/-13.9, OM 40 mg/HCTZ 25 mg: -23.9/-14.5, and AML 10 mg/HCTZ 25 mg: -18.5 mm Hg/-10.7 mm Hg; P<.0001 each). Greater efficacy was also found during daytime and nighttime hours and during the last 6, 4, or 2 hours of the dosing interval. The authors conclude that the triple combination of OM 40 mg/AML 10 mg/HCTZ 25 mg demonstrated superior efficacy and sustained reductions in ABP compared with its dual-combination components.

Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: The TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study.

BACKGROUND: Patients with hypertension may require a combination of > or =2 antihypertensive agents to achieve blood pressure (BP) control. OBJECTIVE: The aim of this study was to determine whether a triple combination of olmesartan medoxomil (OM), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) had a clinically significant benefit compared with dual combinations of the individual components in patients with moderate to severe hypertension. METHODS: This was a multicenter, randomized, doubleblind, parallel-group study in which triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was compared with dual combinations of the individual components-OM 40 mg/AML 10 mg in fixed-dose combination, OM 40 mg/HCTZ 25 mg in fixed-dose combination, and AML 10 mg + HCTZ 25 mg-in patients aged > or =18 years who had a mean seated BP > or =140/100 mm Hg or > or =160/90 mm Hg. The study consisted of a 3-week washout period with no study medication and a 12-week double-blind treatment period. In the first 2 weeks of the double-blind treatment period, all patients were randomized to receive dual combination treatment or placebo. All patients assigned to a dual combination treatment group continued the assigned treatment until week 4, and all patients assigned to placebo were switched at week 2 to receive 1 of the dual combination treatments until week 4. At week 4, patients either continued dual combination treatment or switched to triple combination treatment until week 12. The primary end point was the change in seated diastolic BP (SeDBP) from baseline to week 12; SeDBP reduction of > or =2 mm Hg was considered a clinically significant benefit. Secondary efficacy end points included the change in seated systolic BP (SeSBP) at week 12 and the percentages of patients achieving BP targets of <140/90 mm Hg, <120/80 mm Hg, SeSBP <140 mm Hg, and SeDBP <90 mm Hg at week 12. The tolerability of the treatments was also evaluated based on adverse events (AEs), clinical laboratory evaluations (chemistry, hematology, and urinalysis), physical examinations, and 12-lead ECGs. RESULTS: The 2492 randomized patients (52.9% male, 66.8% white, 30.4% black) had a mean (SD) age of 55.1 (10.9) years and a mean weight of 96.0 (22.9) kg. Diabetes was present in 15.5% of the population, chronic cardiovascular disease in 9.1%, and chronic kidney disease in 4.1%. At baseline, the mean SeBP was 168.5/100.9 mm Hg. At week 12, triple combination treatment was associated with significantly greater least squares mean reductions in SeBP compared with the dual combinations (SeDBP: -21.8 vs -15.1 to -18.0 mm Hg, respectively [P < 0.001]; SeSBP: -37.1 vs -27.5 to -30.0 mm Hg [P < 0.001]). A significantly higher proportion of patients receiving triple combination treatment reached BP targets compared with the dual combinations at week 12 (P < 0.001). The proportions of patients reaching the BP target of <140/90 mm Hg at week 12 was 69.9% in the triple combination treatment group and 52.9%, 53.4%, and 41.1% in the treatment groups receiving OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, and AML 10 mg + HCTZ 25 mg, respectively (P < 0.001, triple combination vs each dual combination). The incidence of treatment-emergent AEs (TEAEs) was 58.4% for triple combination treatment and 51.7% to 58.9% for the dual combinations; most TEAEs were mild or moderate in severity. The most common TEAEs in the triple combination treatment group were dizziness (9.9%), peripheral edema (7.7%), and headache (6.4%). In total, 52 patients (2.3%) discontinued the study due to TEAEs-6 (1.0%) in the OM 40 mg/AML 10 mg group, 12 (2.1%) in the OM 40 mg/HCTZ 25 mg group, 11 (2.0%) in the AML 10 mg + HCTZ 25 mg group, and 23 (4.0%) in the OM 40 mg + AML 10 mg + HCTZ 25 mg group. Thirty-two patients (1.4%)-4 (0.7%), 5 (0.9%), 5 (0.9%), and 18 (3.1%) in the respective treatment groups-discontinued the study due to drug-related TEAEs. CONCLUSIONS: In these adult patients with moderate to severe hypertension, triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was associated with significant BP reductions compared with dual combinations of the individual components. All treatments were generally well tolerated. ClinicalTrials. gov identifier: NCT00649389.

A double-blind, dose-response study of the efficacy and safety of olmesartan medoxomil in children and adolescents with hypertension.

The current study investigated the efficacy and safety of olmesartan medoxomil in children with hypertension, defined as systolic blood pressure measured at or above the 95th percentile (90th percentile for patients with diabetes, glomerular kidney disease, or family history of hypertension) for age, gender, and height while off any antihypertensive medication. The active treatment phase was conducted in 2 periods, with 2 cohorts in each period (cohort A, 62% white; cohort B, 100% Black). In period 1, patients stratified by weight received low-dose (2.5 or 5 mg) or high-dose (20 or 40 mg) olmesartan medoxomil daily for 3 weeks. In period 2, patients maintained their olmesartan medoxomil dose or initiated placebo washout for an additional 2 weeks. Period 1 efficacy results showed a dose-dependent, statistically significant reduction in seated trough systolic and diastolic blood pressure for both cohorts, with mean blood pressure reductions numerically smaller in cohort B than in cohort A. The olmesartan medoxomil dose response remained statistically significant when adjusted for body weight. In period 2, blood pressure control decreased in those patients switching to placebo, whereas patients continuing to receive olmesartan medoxomil therapy maintained consistent blood pressure reduction. Adverse events were generally mild and unrelated to study medication. Olmesartan medoxomil was safe and efficacious in children with hypertension, resulting in significant blood pressure reductions.

Efficacy and safety of long-term treatment with the combination of amlodipine besylate and olmesartan medoxomil in patients with hypertension.

J Clin Hypertens (Greenwich). 2009;11:475-482. (c) 2009 Wiley Periodicals, Inc.The authors report on the 44-week open-label extension of the 8-week, double-blind Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial in 1684 patients. Initial therapy was amlodipine (AML) plus olmesartan medoxomil (OM) 5+40 mg/d, up-titrated to AML+OM 10+40 mg/d plus hydrochlorothiazide (HCTZ) 12.5 mg then 25 mg if patients did not achieve blood pressure (BP) goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes). Baseline mean BP decreased from 164/102 mm Hg to 131/82 mm Hg at end of study, with an overall 66.7% of patients, including those with diabetes, achieving BP goal. The BP goal achievement was 80% for AML+OM 5+40 mg/d, 70.6% for AML+OM 10+40 mg/d, 66.6% for AML+OM+HCTZ 10+40+12.5 mg/d, and 46.3% for AML+OM+HCTZ 10+40+25 mg/d. Study medication was safe and well tolerated. Combination antihypertensive therapy with AML+OM+/-HTCZ, up-titrated as necessary, allowed a majority of patients to achieve BP goal.