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Safety, tolerability, and efficacy of azilsartan medoxomil with or without chlorthalidone during and after 8 months of treatment for hypertension.

ABSTRACT: A phase 3, 26-week, open-label, titrate-to-target study (n=418) assessed the safety of azilsartan medoxomil (AZL-M) alone and with chlorthalidone (CLD), followed by a 6-week, double-blind, placebo-controlled reversal phase with change in clinic diastolic blood pressure (DBP) as the primary endpoint. Target blood pressure (BP) was <140/90 mm Hg (<130/80 mm Hg with diabetes/chronic kidney disease). AZL-M was initiated at 40 mg once a day (QD), force-titrated to 80 mg at week 4. CLD 25 mg QD could be added (weeks 8-22), if required, to reach target, followed by additional antihypertensives from week 12. At the end of the open-label phase, mean change in systolic BP (SBP)/DBP from baseline was -23/-16 mm Hg. The most common adverse events, irrespective of treatment, were dizziness (8.9%) and headache (7.2%). Serious AEs were reported in eight patients (1.9%). Consecutive creatinine elevations ≥50% with values exceeding the upper limit of normal (ULN) were reported in nine (2.2%) patients. All returned to below the 50% threshold; most also returned to below the ULN after drug discontinuation. Mean DBP was maintained through the reversal phase in patients receiving AZL-M, but increased with placebo (difference: -7.8 mm Hg, 95% confidence interval, -9.8 to -5.8; P<.001). AZL-M alone or with CLD showed good long-term safety and stable BP improvements in a titrate-to-target approach. BP improvements caused by AZL-M therapy were safely reversible upon AZL-M withdrawal.

SUBMITTER: Kipnes MS

PROVIDER: S-EPMC5024056 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Long-term efficacy and tolerability of azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide in chronic kidney disease.

Project description:An open-label, long-term study evaluated safety and tolerability of azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs olmesartan/hydrochlorothiazide (OLM/HCTZ) in hypertensive participants with stage 3 chronic kidney disease. Initial therapy was AZL-M/CLD 20/12.5 mg (n = 77) or OLM/HCTZ 20/12.5 mg (n = 76), but could be up-titrated (AZL-M/CLD to 40/25 mg; OLM/HCTZ to 40/25 mg [US] or 20/25 mg [Europe]) with other agents added during weeks 4-52. Primary endpoint was proportion of participants with ≥ 1 adverse event (AE) through week 52. Baseline demographics were similar. AEs did not differ between groups (88.3%, AZL-M/CLD vs 76.3%, OLM/HCTZ; P = .058). AZL-M/CLD showed greater systolic BP reductions after initial dosing (P = .037) but not during long-term follow-up (P = .588). A greater proportion of participants up-titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL-M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Both AZL-M/CLD and OLM/HCTZ showed similar efficacy and tolerability.

| S-EPMC8031057 | biostudies-literature

A randomized trial of the efficacy and safety of azilsartan medoxomil combined with chlorthalidone.

Project description:INTRODUCTION:We measured the effects of azilsartan medoxomil co-administered with chlorthalidone 25 mg in stage 2 hypertension. METHODS:Azilsartan medoxomil 40 or 80 mg plus chlorthalidone were compared with placebo plus chlorthalidone once daily in a randomized, double-blind, 6-week trial. The primary endpoint was change from baseline in 24-hour mean systolic blood pressure by ambulatory blood pressure monitoring. RESULTS:Patients ( N=551; mean age 59 years; 51.7% men) were randomly assigned to placebo plus chlorthalidone ( n=184), azilsartan medoxomil 40 mg plus chlorthalidone ( n=185), or azilsartan medoxomil 80 mg plus chlorthalidone ( n=182). Baseline systolic blood pressures were similar among groups. After 6 weeks, least squares mean (standard error) reductions with azilsartan medoxomil 40 mg and 80 mg plus chlorthalidone were similar in magnitude (-31.7 (1.0) and -31.3 (1.0) mmHg, respectively), but greater than chlorthalidone alone (-15.9 (1.0) mmHg). Hypotension and serum creatinine elevations were more frequent with azilsartan medoxomil plus chlorthalidone than chlorthalidone alone (reversed with drug discontinuation). Notably, plasma potassium reduction of 0.43 meq/L with chlorthalidone was attenuated to 0.13 and 0.05 meq/L by azilsartan medoxomil 40 mg and 80 mg, respectively. CONCLUSION:Azilsartan medoxomil 40 mg or 80 mg plus chlorthalidone 25 mg was significantly more efficacious than chlorthalidone alone in reducing blood pressure and was well tolerated. Clinicaltrial.gov , https://clinicaltrials.gov/ct2/show/NCT00591773 , NCT00591773.

| S-EPMC6122257 | biostudies-literature

Comparison of long-term safety of fixed-dose combinations azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide.

Project description:This 52-week, randomized, open-label study evaluated long-term safety/tolerability of fixed-dose combination azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs fixed-dose combination olmesartan medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with essential hypertension (stage 2; clinic systolic blood pressure 160-190 mm Hg). Initial AZL-M/CLD 40/12.5 mg/d (n=418) or OLM/HCTZ 20/12.5 mg/d (n=419) could be uptitrated during weeks 4 to 52 (AZL-M/CLD to 80/25 mg; OLM/HCTZ to 40/25 mg [United States] or 20/25 mg [Europe]) to meet blood pressure targets. Treatment-emergent adverse events/serious adverse events occurred in 78.5%/5.7% of patients taking AZL-M/CLD vs 76.4%/6.2% taking OLM/HCTZ. The most frequent adverse events were dizziness (16.3% vs 12.6%), blood creatinine increase (21.5% vs 8.6%), headache (7.4% vs 11.0%), and nasopharyngitis (12.2% vs 11.5%). Hypokalemia was uncommon (1.0% vs 0.7%). Greater blood pressure reductions with AZL-M/CLD by week 2 were maintained throughout the study, despite less uptitration (32.3% vs 48.9% with OLM/HCTZ). Fixed-dose combination AZL-M/CLD showed an encouraging benefit-risk profile when used per standard clinical practice in a titrate-to-target strategy.

| S-EPMC8031288 | biostudies-literature

Efficacy and safety of azilsartan medoxomil, an angiotensin receptor blocker, in Korean patients with essential hypertension.

Project description:BackgroundThis was a phase 3, randomized, double-blind, placebo-controlled study.MethodsAdult Korean patients with essential hypertension and a baseline mean sitting clinic systolic blood pressure (scSBP) ≥150 and ≤180 mmHg were randomized to 6-week treatment with placebo (n = 65), azilsartan medoxomil (AZL-M) 40 mg (n = 132), or AZL-M 80 mg (n = 131). The primary endpoint was the change from baseline to week 6 in trough scSBP.ResultsThe least-squares mean (standard error) change from baseline in trough scSBP in the placebo, AZL-M 40-mg, and 80-mg groups at week 6 were - 8.8 (2.00), - 22.1 (1.41), and - 23.7 (1.40) mmHg, respectively (p < 0.001 for AZL-M 40 and 80 mg vs placebo). No clinically meaningful heterogeneity in efficacy was observed between subgroups (age, sex, diabetes status) and the overall population. Treatments were well tolerated and adverse events were similar between groups.ConclusionsResults of this study confirm a positive benefit-risk profile of AZL-M for essential hypertension in Korean adults.Trial registrationClinicaltrial.gov; identifier number: NCT02203916. Registered July 28, 2014 (retrospectively registered).

| S-EPMC5804062 | biostudies-literature

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study.

Project description:This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100?mmHg). All subjects (n?=?669) initiated AZL-M 40?mg QD, force-titrated to 80?mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25?mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5-25?mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4?mmHg (Cohort 1) and 24.2/17.9?mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics.

| S-EPMC4819839 | biostudies-literature

Efficacy and safety of azilsartan medoxomil/chlortalidone fixed-dose combination in hypertensive patients uncontrolled on azilsartan medoxomil alone: A randomized trial.

Project description:Patients with grade 2-3 essential hypertension and postplacebo mean clinic systolic blood pressure (SBP) 160-190 mm Hg and 24-hour SBP 140-175 mm Hg by ambulatory blood pressure monitoring (ABPM) received 40 mg azilsartan medoxomil (AZL-M) monotherapy for 4 weeks. "Nonresponders" were then randomized to 8 weeks of double-blind treatment with AZL-M 40 mg, AZL-M/chlortalidone (CLD) 40/25, or AZL-M/CLD 40/12.5 mg. After 8 weeks, mean clinic SBP change was -21.1 (±1.04) mm Hg for AZL-M/CLD 40/25 mg, -15.8 (±1.08) mm Hg for AZL-M/CLD 40/12.5 mg, and -6.4 (±1.05) mm Hg for AZL-M 40 mg (P < 0.001 for both AZL-M/CLD vs AZL-M, ANCOVA). Drug discontinuation rates were 8.9% (AZL-M/CLD 40/25 mg), 7.5% (AZL-M 40 mg), and 3.9% (AZL-M/CLD 40/12.5 mg). Creatinine increased in 8.1% (AZL-M/CLD 40/25), 3.1% (AZL-M/CLD 40/12.5 mg), and 3.0% (AZL-M 40 mg) of patients. AZL-M/CLD was effective and well tolerated in patients not achieving blood pressure targets with AZL-M.

| S-EPMC8030929 | biostudies-literature

A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension.

Project description:BACKGROUND:Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). OBJECTIVE/METHODS:We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160-190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. RESULTS:Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (-37.6 and -38.2 mmHg) versus OLM/HCTZ (-31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (-26.4 and -27.9 versus -20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively. CONCLUSION:This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ.

| S-EPMC5862000 | biostudies-literature

Clinical utility of azilsartan-chlorthalidone fixed combination in the management of hypertension.

Project description:Azilsartan-chlorthalidone fixed combination is a new drug in the management of hypertension. Azilsartan has been shown to have greater blood pressure-lowering effects than other angiotensin-receptor blockers (ARBs), and the debate regarding the superiority of chlorthalidone over hydrochlorothiazide has been ongoing for years. The combination is unique because it is the first to partner an ARB with this, possibly more effective, diuretic. This review will address trials involving both components of this drug, as well as phase III trials involving the fixed-combination product. The article will also discuss the benefit of combination therapy in the treatment of hypertension.

| S-EPMC3383350 | biostudies-other

Single-dose pharmacokinetics and safety of azilsartan medoxomil in children and adolescents with hypertension as compared to healthy adults.

Project description:PurposeThis open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12-16 years [cohort 1a; n = 9]; 6-11 years [cohort 2; n = 8]; 4-5 years [cohort 3; n = 3]).MethodsModel-based simulations were performed to guide dosing, especially in 1-5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20-60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg.ResultsExposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized C max and AUC0-∞, was ∼15-30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8-25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25-50-kg subjects require half the adult dose (10-40 mg), whereas 50-100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine).ConclusionsThis dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).

| S-EPMC4792355 | biostudies-literature

Efficacy and tolerability of amlodipine plus olmesartan medoxomil in patients with difficult-to-treat hypertension.

Project description:Hypertension is particularly prevalent in patients aged ?65 years, those with a body mass index ?30?kg?m(-2), Blacks and those with type II diabetes. Here we report a prespecified secondary analysis of the efficacy of amlodipine (10?mg?day(-1)), olmesartan medoxomil (40?mg?day(-1)), a combination of the two and placebo in these subgroups. Patients were randomized to treatment for 8 weeks. The primary efficacy endpoint was the change from baseline in mean seated diastolic blood pressure (DBP). Secondary efficacy endpoints included the change from baseline in mean seated systolic BP (SBP), proportions of patients achieving BP goal (<140/90?mm?Hg or <130/80?mm?Hg in patients with diabetes), and the number and percentage of patients achieving a range of BP targets. Safety and tolerability of amlodipine 5 and 10?mg, olmesartan medoxomil 10, 20 and 40?mg, and all possible combinations of the two were also assessed. For each prespecified subgroup, all active treatments resulted in significant BP reductions from baseline (P<0.05). The antihypertensive effect of the combination of amlodipine+olmesartan medoxomil was generally greater than the constituent amlodipine or olmesartan medoxomil monotherapies, regardless of subgroup. In general, more patients receiving combination therapy achieved BP goal than those treated with monotherapies. The safety and tolerability of combinations were similar to monotherapies across the subgroups. These results suggest that the combination of amlodipine+olmesartan medoxomil provides a safe and effective option for the treatment of hypertension in challenging patient populations.

| S-EPMC2963900 | biostudies-other

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