Abstract
In this phase 2, multicenter, parallel‐group, double‐blind, dose‐ranging study, hypertensive adults (n=449) were randomized to receive one of five doses of a capsule formulation of azilsartan medoxomil (AZL‐M; 5, 10, 20, 40, 80 mg), olmesartan medoxomil (OLM) 20 mg, or placebo once daily. The primary endpoint was change in trough clinic diastolic blood pressure (DBP) at week 8. AZL‐M provided rapid statistically and clinically significant reductions in DBP and systolic blood pressure (SBP) vs placebo at all doses except 5 mg. Placebo‐subtracted changes were greatest with the 40 mg dose (DBP, −5.7 mm Hg; SBP, −12.3 mm Hg). Clinic changes with AZL‐M (all doses) were statistically indistinguishable vs OLM, although there were greater reductions with AZL‐M 40 mg using 24‐hour ambulatory blood pressure. Adverse event frequency was similar in the AZL‐M and placebo groups. Based on these and other findings, subsequent trials investigated the commercial AZL‐M tablet in the dose range of 20 to 80 mg/d.
Despite the wide array of available antihypertensive drug options, blood pressure (BP) control remains suboptimal in many patients with hypertension, and most patients require multidrug therapy to achieve BP goals.1, 2 Consequently, the cardiovascular disease burden associated with hypertension remains substantial and there continues to be a real need for improved BP‐lowering strategies and better use of the most effective and well‐tolerated available antihypertensive therapies.3
As a class, the angiotensin II receptor blockers (ARBs) are generally considered to be among the more effective BP‐lowering drugs and among the best tolerated, albeit with some differences between individual agents.4, 5, 6, 7, 8, 9 Furthermore, along with other renin‐angiotensin system (RAS) inhibitors, there is good evidence to show that ARBs improve renal outcomes compared with other antihypertensive drug classes in patients with chronic kidney disease.10, 11 Consequently, ARBs feature highly in hypertension treatment guidelines as a recommended first‐ or second‐line treatment option for many patients with hypertension, especially those with renal impairment.10, 11
The latest ARB and eighth drug in the class, azilsartan medoxomil (AZL‐M), is approved for the treatment of hypertension at a dose of 20 to 80 mg once daily (40–80 mg in the United States), alone or in combination with other antihypertensive agents.12, 13, 14, 15, 16, 17, 18 This ARB is a prodrug that is rapidly hydrolyzed during absorption in the gut to form its active moiety azilsartan (AZL).19, 20 The estimated absolute bioavailability of AZL following oral administration of AZL‐M is approximately 60%, with peak plasma concentrations achieved in 1.5 to 3.0 hours, a volume of distribution of around 16 L, and an elimination half‐life of approximately 11 hours.12, 13 A nonprodrug formulation of AZL is available for clinical use in Japan.19, 20 Similar to other ARBs, AZL has a high affinity for the angiotensin type 1 (AT1) receptor and high selectivity relative to the type 2 (AT2) receptor, although AZL appears to dissociate more slowly from the AT1 receptor compared with other ARBs, which has the potential to confer greater and longer‐lasting antihypertensive effects.19, 20, 21, 22
During its development, AZL was investigated using various formulations, including an AZL‐M (prodrug) capsule and an AZL (nonprodrug) tablet, which differ from the final commercially approved AZL‐M tablet formulation.23 The AZL‐M capsule and AZL tablet provide approximately 60% and 162% systemic AZL exposure, respectively, compared with the commercial AZL‐M tablet under fasting conditions.23 With the AZL‐M capsule, food increases AZL exposure and also increases variability in exposure, whereas the AZL‐M tablet has the advantage that it is unaffected by food.23
Phase 2 dose‐ranging studies were performed using the AZL‐M capsule and AZL tablet formulations only, and these provided the basis for dosing in the subsequent phase 3 studies using the AZL‐M tablet. The current study evaluated the BP‐lowering dose‐response relationship of the AZL‐M capsule formulation in patients with essential hypertension. The phase 2 study evaluating the AZL tablet has been published separately.
Research Design and Methods
Study Design
This was a phase 2, multicenter, randomized, parallel‐group, double‐blind, placebo‐controlled, dose‐ranging study (ClinicalTrials.gov identifier: NCT00362115) consisting of a 7‐day screening period, a 14‐day single‐blind placebo run‐in, and 8 weeks of double‐blind treatment. The study was performed at 76 centers in the United States, Mexico, Argentina, and Peru and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The applicable institutional review boards or ethics committees approved the study and all patients gave written informed consent to participate.
Study Participants
Men and women aged 18 years and older with mild to moderate uncomplicated essential hypertension (diastolic BP [DBP] ≥95 and ≤114 mm Hg at the start of placebo run‐in and the randomization visit) were included in the current study. Participants were required to discontinue their current antihypertensive medication(s), if any, 3 weeks before randomization. Clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) had to be within the reference ranges for the testing laboratory. The main exclusion criteria were: systolic BP (SBP) >180 mm Hg; a decrease of ≥8 mm Hg in clinic DBP between the start of the placebo run‐in and the randomization visit; hypersensitivity to ARBs; clinically relevant history of cardiovascular disease (eg, atrial fibrillation or flutter); night‐shift work; secondary hypertension of any etiology; significant, moderate to severe renal dysfunction or disease; history of cancer that had not been in remission for at least the previous 5 years; history of drug or alcohol abuse; poorly controlled diabetes; and alanine aminotransferase >2.5 times the upper limit of normal, active liver disease, or jaundice. Pregnant or lactating women were also excluded. Excluded medications included diuretics, vasodilators, phosphodiesterase‐5 inhibitors, thiazolidinediones, tricyclic antidepressants, lithium, monoamine oxidase inhibitors, phenothiazines, diet medications, amphetamines or their derivatives, and chronic use of common cold medications or nonsteroidal anti‐inflammatory drugs, including aspirin >325 mg/d or cyclooxygenase‐2 inhibitors.
Treatment Allocation
A centralized interactive voice‐activated response system was used for patient randomization and study medication assignments stratified by race (black vs nonblack). Patients were randomized in equal ratios to receive double‐blind treatment with one of five dose levels of AZL‐M (5, 10, 20, 40, or 80 mg), the reference treatment (OLM 20 mg), or placebo once per day in the morning with food for 8 weeks. The AZL‐M study medication was supplied as 5 and 20 mg capsules and corresponding placebo capsules; OLM was supplied as 20 mg overencapsulated (O/E) capsules with matching placebo capsules. Each dose was administered as a total of five capsules (four AZL‐M and/or matching placebo capsules plus one OLM O/E or matching placebo capsule).
Endpoints and Assessments
The primary efficacy endpoint was the change in sitting trough clinic DBP from baseline to week 8. Secondary efficacy endpoints included sitting trough SBP (clinic), standing trough SBP and DBP (clinic), and SBP and DBP based on 24‐hour ambulatory BP monitoring (ABPM). For ABPM, the daytime while awake period was defined as 6 am to 10 pm, the nighttime while asleep period was defined as 12 am to 6 am and the trough period was defined as the last 2 hours of the 24‐hour dosing period. ABPM measurements were summarized by overall 24‐hour mean values; 0‐ to 12‐hour, 10‐ to 12‐hour, and 24‐ to 36‐hour mean values; daytime while awake and nighttime while asleep mean values; and 22‐ to 24‐hour and 34‐ to 36‐hour trough mean values. Safety variables included adverse events (AEs; including incidence of symptomatic hypotension), clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital signs, physical examination, electrocardiography results, and use of concomitant medications. All patients who received at least one dose of double‐blind study medication were included in the safety analysis.
Clinic BP and measurements (three seated after 5 minutes of sitting, one standing after 2 minutes of standing) were taken approximately 24 hours after the previous dose, and prior to dosing or blood collection on the day of double‐blind therapy visits. Measurements were performed with either a standard mercury sphygmomanometer (the preferred method) or a certified automated (and calibrated) BP device using an appropriate cuff size. Devices designed to measure BP from the finger or wrist were not used. A printed BP report was obtained for each recording to minimize the potential for variability between operators.
Baseline ABPM was conducted over a 24‐hour period on study day 1 and the patient was instructed to start double‐blind dosing the morning after the ABPM was complete. For the follow‐up ABPM measurement (week 8 or final visit) the investigator administered clinic dosing at 8 am (±2 hours) prior to starting the 24‐hour ABPM. The portable ABPM units (Model 90207 ABP System, Spacelabs Healthcare, Snoqualmie, WA) with a hook‐up and data transfer instructions were all provided by a core laboratory (Integrium, LLC, Tustin, CA), and were programmed and calibrated (for each patient) by the investigator or designee to measure BP and heart rate at set intervals during the day and night. The ABPM recorder obtained readings every 15 minutes during 6 am to 10 pm (to coincide with the daytime, awake period) and every 20 minutes during 10 pm to 6 am (to coincide with the nighttime, sleeping period). If the ABPM recordings did not meet the minimal quality control criteria of: (1) a “Beginning of Test” time between 6 am and 10 pm, (2) a monitoring period ≥24 hours in duration, (3) ≥70 valid readings (80% acceptance rate), and (4) no more than two nonconsecutive hours were missing a valid reading, they were repeated once within 3 days. Measurements were stored on the device and later uploaded onto a computer. If the patient terminated early from the study, then the site attempted to complete ABPM prior to discontinuing study drug and initiating additional antihypertensive therapy if the patient completed at least 4 weeks of double‐blind therapy. If day 1 ABPM was unsuccessful, follow‐up ABPM was not required.
Statistical Analysis
Data analysis, tabulations of descriptive statistics and inferential statistics were performed using SAS version 8.02 (SAS Institute, Cary, NC). All efficacy analyses were based on the full analysis set (FAS), defined as all randomized patients who received at least one dose of double‐blind study medication. A patient was included in the analyses of a specific variable only when there was both a baseline value and at least one value obtained during the double‐blind treatment period. Analysis of change from baseline was based on both observed values and a last observation carried forward method.
Treatment group comparisons (active drug vs placebo or AZL‐M vs OLM) for change from baseline in efficacy variables were carried out using analysis of covariance (ANCOVA) with terms for treatment and baseline value (as a covariate) in the model. P values, least squares (LS) means, and 95% confidence intervals (CIs) for treatment differences in change from baseline were estimated within the framework of ANCOVA. A sample size of 420 participants (60 per treatment group) was calculated as sufficient to have ≥80% power to detect a difference of 5 mm Hg in change from baseline DBP between the active and placebo treatment groups with a 5% two‐sided significance level, assuming a common standard deviation of 8.5 mm Hg and a 15% dropout rate.
Results
Patient Characteristics
A total of 812 patients were screened, 533 entered the placebo run‐in, and 449 were randomized into the study (Figure S1). Of the 449 randomized patients, all but four received double‐blind medication and were included in the safety population; three patients were excluded from the FAS because of the lack of postbaseline values. Demographic and baseline characteristics for the patient population were well matched between the different groups and are summarized in Table 1. Mean age was approximately 55 years, mean body mass index was around 30 kg/m2, 77% were white, and there were similar numbers of men and women. Mean baseline clinic BP was approximately 150/100 mm Hg. Baseline measurements based on ABPM were lower than clinic measurements, with the lowest values seen during the nighttime period.
Table 1.
Demographic and Baseline Characteristics of the Full Analysis Set Population
| Demographic Variable | Placebo (n=61) | AZL‐M 5 mg (n=65) | AZL‐M 10 mg (n=63) | AZL‐M 20 mg (n=64) | AZL‐M 40 mg (n=62) | AZL‐M 80 mg (n=64) | OLM 20 mg (n=63) |
|---|---|---|---|---|---|---|---|
| Female/male, % | 52/48 | 45/55 | 51/49 | 47/53 | 53/47 | 44/56 | 54/46 |
| White/black/other race, % | 80/10/11a | 77/14/9 | 73/13/14 | 78/13/9 | 79/11/10 | 77/14/9 | 76/14/11b |
| Age, y | 56.0±11.4 | 54.0±10.0 | 56.5±8.5 | 54.6±9.1 | 55.3±9.8 | 53.5±11.0 | 53.4±11.0 |
| BMI, kg/m2 | 31.0±5.3 | 29.4±5.0 | 30.0±5.9 | 31.2±5.6 | 31.5±5.7 | 31.4±6.3 | 29.3±5.5 |
| Body weight, kg | 86.3±18.0 | 83.3±20.8 | 82.7±19.0 | 87.6±17.9 | 87.2±18.1 | 87.3±20.8 | 80.6±15.8 |
| Sitting trough clinic BP, mm Hg | |||||||
| DBP | 100.1±4.5 | 99.8±4.2 | 99.4±4.0 | 99.7±5.2 | 99.7±3.9 | 100.3±4.8 | 99.8±4.2 |
| SBP | 150.8±13.2 | 150.2±12.9 | 152.4±12.5 | 149.1±11.2 | 150.6±12.8 | 151.2±12.8 | 150.3±11.2 |
| ABPM variables, mm Hgc | |||||||
| 24‐h DBP | 86.5±9.4 | 86.8±10.9 | 85.3±11.0 | 86.6±11.4 | 86.0±10.1 | 86.5±9.6 | 88.4±10.5 |
| Daytime (awake) DBP | 89.8±9.9 | 91.3±10.9 | 89.3±10.5 | 90.5±11.4 | 89.5±10.3 | 89.8±9.3 | 92.5±10.9 |
| Nighttime (asleep) DBP | 79.3±10.9 | 77.7±12.5 | 76.7±12.7 | 78.3±13.1 | 78.2±11.3 | 79.4±11.3 | 79.2±11.6 |
| Trough DBPb | 91.6±12.4 | 93.4±11.5 | 90.0±10.6 | 91.3±12.8 | 90.5±13.2 | 90.7±12.1 | 93.1±13.6 |
| 24‐h SBP | 143.0±11.5 | 140.9±14.9 | 140.1±14.7 | 140.3±12.7 | 141.0±12.6 | 141.0±16.5 | 141.3±13.8 |
| Daytime (awake) SBP | 146.7±11.7 | 146.1±14.3 | 144.5±14.4 | 144.6±13.1 | 144.6±12.9 | 144.7±16.7 | 145.9±14.4 |
| Nighttime (asleep) SBP | 134.6±14.6 | 129.5±17.5 | 130.4±17.7 | 130.9±14.2 | 132.2±15.1 | 132.9±18.1 | 131.0±16.9 |
| Trough SBPb | 147.8±16.7 | 147.1±15.7 | 143.8±15.2 | 144.4±15.5 | 144.3±16.9 | 144.9±19.6 | 145.9±18.4 |
| Previous antihypertensive treatmentd | |||||||
| Amiloride | 0 | 0 | 1 (1.6) | 1 (1.6) | 1 (1.6) | 0 | 1 (1.6) |
| Amlodipine | 10 (15.9) | 4 (6.2) | 4 (6.3) | 1 (1.6) | 7 (11.3) | 8 (12.5) | 7 (11.1) |
| Amlodipine besilate | 0 | 3 (4.6) | 1 (1.6) | 0 | 0 | 0 | 1 (1.6) |
| Amlodipine/benazepril | 1 (1.6) | 2 (3.1) | 0 | 2 (3.1) | 3 (4.8) | 0 | 0 |
| Atenolol | 3 (4.8) | 4 (6.2) | 4 (6.3) | 2 (3.1) | 4 (6.5) | 6 (9.4) | 8 (12.7) |
| Benazepril | 0 | 0 | 1 (1.6) | 1 (1.6) | 0 | 2 (3.1) | 1 (1.6) |
| Benazepril hydrochloride | 0 | 1 (1.5) | 0 | 0 | 0 | 0 | 0 |
| Bisoprolol | 1 (1.6) | 0 | 0 | 0 | 0 | 0 | 0 |
| Candesartan/HCTZ | 0 | 0 | 0 | 0 | 0 | 1 (1.6) | 0 |
| Candesartan | 0 | 0 | 1 (1.6) | 0 | 0 | 0 | 2 (3.2) |
| Candesartan cilexetil | 0 | 2 (3.1) | 0 | 0 | 0 | 0 | 0 |
| Captopril | 2 (3.2) | 2 (3.1) | 2 (3.1) | 2 (3.1) | 1 (1.6) | 1 (1.6) | 6 (9.5) |
| Carvedilol | 2 (3.2) | 1 (1.5) | 0 | 1 (1.6) | 2 (3.2) | 1 (1.6) | 1 (1.6) |
| Chlorthalidone | 1 (1.6) | 1 (1.5) | 1 (1.6) | 4 (6.3) | 2 (3.2) | 2 (3.1) | 2 (3.2) |
| Clonidine | 1 (1.6) | 0 | 0 | 0 | 0 | 0 | 0 |
| Diltiazem | 1 (1.6) | 0 | 2 (3.1) | 0 | 0 | 1 (1.6) | 1 (1.6) |
| Doxazosin | 0 | 0 | 0 | 0 | 1 (1.6) | 0 | 0 |
| Dyazide | 0 | 0 | 0 | 0 | 1 (1.6) | 1 (1.6) | 0 |
| Enalapril | 8 (12.7) | 10 (15.4) | 11 (17.2) | 11 (17.2) | 10 (16.1) | 12 (18.8) | 13 (20.6) |
| HCTZ | 15 (23.8) | 16 (24.6) | 13 (20.3) | 12 (18.8) | 13 (21.0) | 13 (20.3) | 13 (20.6) |
| Irbesartan | 3 (4.8) | 1 (1.5) | 1 (1.6) | 2 (3.1) | 2 (3.2) | 1 (1.6) | 1 (1.6) |
| Irbesartan/HCTZ | 2 (3.2) | 0 | 0 | 0 | 0 | 0 | 0 |
| Labetalol | 0 | 0 | 0 | 0 | 0 | 1 (1.6) | 0 |
| Lisinopril | 6 (9.5) | 3 (4.6) | 1 (1.6) | 5 (7.8) | 3 (4.8) | 0 | 4 (6.3) |
| Lisinopril/HCTZ | 0 | 0 | 0 | 3 (4.7) | 1 (1.6) | 0 | 2 (3.2) |
| Losartan | 1 (1.6) | 1 (1.5) | 3 (4.7) | 6 (9.4) | 3 (4.8) | 3 (4.7) | 1 (1.6) |
| Losartan potassium | 0 | 0 | 1 (1.6) | 0 | 0 | 0 | 1 (1.6) |
| Losartan/HCTZ | 0 | 1 (1.5) | 0 | 0 | 0 | 1 (1.6) | 0 |
| Methyldopa | 0 | 0 | 0 | 0 | 1 (1.6) | 0 | 0 |
| Metoprolol | 0 | 3 (4.6) | 0 | 1 (1.6) | 1 (1.6) | 2 (3.1) | 0 |
| Metoprolol succinate | 0 | 1 (1.5) | 0 | 1 (1.6) | 0 | 0 | 0 |
| Nifedipine | 0 | 2 (3.1) | 0 | 3 (4.7) | 0 | 2 (3.1) | 0 |
| Nimodipine | 0 | 1 (1.5) | 0 | 0 | 0 | 0 | 0 |
| Nisoldipine | 1 (1.6) | 1 (1.5) | 0 | 1 (1.6) | 0 | 0 | 0 |
| Olmesartan | 2 (3.2) | 3 (4.6) | 3 (4.7) | 1 (1.6) | 4 (6.5) | 1 (1.6) | 0 |
| Olmesartan medoxomil | 0 | 0 | 1 (1.6) | 1 (1.6) | 1 (1.6) | 0 | 0 |
| Perindopril | 1 (1.6) | 0 | 0 | 1 (1.6) | 0 | 0 | 1 (1.6) |
| Propanolol | 0 | 0 | 0 | 0 | 0 | 1 (1.6) | 0 |
| Propanolol/HCTZ | 0 | 0 | 0 | 0 | 0 | 1 (1.6) | 0 |
| Quinapril | 0 | 0 | 0 | 0 | 1 (1.6) | 1 (1.6) | 0 |
| Ramipril | 0 | 1 (1.5) | 1 (1.6) | 1 (1.6) | 2 (3.2) | 1 (1.6) | 0 |
| Telmisartan | 3 (4.8) | 5 (7.7) | 5 (7.8) | 2 (3.1) | 0 | 1 (1.6) | 0 |
| Terazosin | 0 | 1 (1.5) | 0 | 0 | 0 | 0 | 0 |
| Udramil | 0 | 0 | 1 (1.6) | 0 | 0 | 0 | 0 |
| Valsartan | 0 | 4 (6.2) | 0 | 2 (3.1) | 8 (12.9) | 5 (7.8) | 5 (7.9) |
| Valsartan/HCTZ | 0 | 0 | 2 (3.1) | 0 | 0 | 0 | 0 |
| Verapamil or verapamil HCl | 3 (4.8) | 0 | 3 (4.7) | 3 (4.7) | 1 (1.6) | 2 (3.1) | 1 (1.6) |
Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure. Other=Native American, Asian, or Pacific Islander.
Values are expressed as mean±standard deviation unless otherwise indicated. aIncluding one multiracial patient, classified in more than one category. bTrough using the last 2 hours of the dosing interval. cThe number of patients with valid baseline ambulatory blood pressure monitoring (ABPM) recordings were placebo (n=61), azilsartan medoxomil (AZL‐M) 5 mg (n=63), AZL‐M 10 mg (n=62), AZL‐M 20 mg (n=60), AZL‐M 40 mg (n=58), AZL‐M 80 mg (n=62), and olmesartan medoxomil (OLM) 20 mg (n=59). dSafety population; there was a 3‐week washout (1‐week screening period and 2‐week placebo run‐in) of all previous cardiovascular medications.
Between 70.3% and 79.4% of patients in each treatment group received cardiovascular medication; hydrochlorothiazide and enalapril were the most commonly used (Table 1). Fewer patients in the AZL‐M 5, 10, and 20 mg groups reported prior use of amlodipine than patients in the other treatment groups.
Efficacy
A total of 404 patients (90%) completed the study; the most common reasons for premature discontinuation were voluntary withdrawal and lack of efficacy (Figure S1). The mean treatment duration ranged from 7.3 weeks in the OLM 20 mg group to 7.6 weeks in the AZL‐M 5 mg group. At doses of 10, 20, 40, and 80 mg, AZL‐M provided significant reductions in sitting clinic DBP relative to placebo from baseline to week 8 (primary endpoint; Figure 1, Table 2). Statistically significant DBP reductions relative to placebo occurred as early as week 1 and/or 2 in all AZL‐M treatment groups. The greatest DBP treatment effect (relative to placebo) was observed in the AZL‐M 40 mg treatment group. There were no statistically significant differences in the decrease in sitting DBP between any of the AZL‐M treatment groups and the OLM 20 mg treatment group (Figure 1, Table 2). At AZL‐M doses above 5 mg, the effect on sitting DBP did not appear to be dose‐dependent (Figure 1).
Figure 1.
Changes from baseline in sitting clinic diastolic blood pressure over 8 weeks. The top panel shows least squares (LS) mean change±standard error (SE) at 8 weeks (last observation carried forward). The bottom panel shows LS mean change±SE over 8 weeks (observed cases). AZL‐M indicates azilsartan medoxomil; OLM, olmesartan medoxomil. *P<.05 vs placebo. ***P<.001 vs placebo.
Table 2.
Between‐Group Comparisons for Efficacy Variables in the Full Analysis Set
| AZL‐M 5 mg | AZL‐M 10 mg | AZL‐M 20 mg | AZL‐M 40 mg | AZL‐M 80 mg | OLM 20 mg | |
|---|---|---|---|---|---|---|
| Clinic sitting, No. | 63 | 63 | 63 | 61 | 63 | 63 |
| ΔDBP vs placebo | −2.9 (−6.0 to 0.2) | −5.3 (−8.3 to −2.2)a | −3.7 (−6.7 to −0.6)b | −5.7 (−8.8 to −2.6)a | −3.7 (−6.8 to −0.7)b | −3.2 (−6.2 to −0.1)b |
| ΔDBP vs OLM | 0.3 (−2.7 to 3.3) | −2.1 (−5.1 to 0.9) | −0.5 (−3.5 to 2.5) | −2.5 (−5.6 to 0.5) | −0.5 (−3.5 to 2.5) | – |
| ΔSBP vs placebo | −6.1 (−10.8 to −1.4)b | −10.8 (−15.5 to −6.1)a | −9.8 (−14.5 to −5.1)a | −12.3 (−17.0 to −7.5)a | −8.5 (−13.2 to −3.8)a | −8.7 (−13.4 to −4.0)a |
| ΔSBP vs OLM | 2.6 (−2.1 to 7.2) | −2.1 (−6.7 to 2.5) | −1.1 (−5.8 to 3.5) | −3.6 (−8.3 to 1.1) | 0.2 (−4.4 to 4.8) | – |
| 0 to 24‐h ABPM, No. | 56 | 45 | 47 | 41 | 45 | 50 |
| ΔDBP vs placebo | −5.4 (−8.1 to −2.7)a | −8.5 (−11.3 to −5.7)a | −8.7 (−11.5 to −5.9)a | −10.8 (−13.7 to −7.9)a | −9.5 (−12.3 to −6.6)a | −7.4 (−10.2 to −4.7)a |
| ΔDBP vs OLM | 2.0 (−0.6 to 4.6) | −1.0 (−3.8 to 1.7) | −1.3 (−4.0 to 1.4) | −3.4 (−6.2 to −0.6)b | −2.0 (−4.8 to 0.7) | – |
| ΔSBP vs placebo | −8.5 (−12.5 to −4.5)a | −13.1 (−17.3 to −8.9)a | −12.1 (−16.3 to −8.0)a | −16.8 (−21.1 to −12.5)a | −13.4 (−17.6 to −9.2)a | −10.3 (−14.4 to −6.2)a |
| ΔSBP vs OLM | 1.7 (−2.1 to 5.6) | −2.9 (−6.9 to 1.2) | −1.9 (−5.9 to 2.2) | −6.5 (−10.7 to −2.4)c | −3.1 (−7.2 to 0.9) | – |
Abbreviations: AZL‐M, azilsartan medoxomil; DBP, diastolic blood pressure; OLM, olmesartan medoxomil; SBP, systolic blood pressure. All data are expressed as least squares mean (95% confidence interval) (mm Hg) at week 8 last observation carried forward (clinic measurements) or final visit (ambulatory blood pressure monitoring [ABPM]). a P<.001. b P<.05. c P<.01.
All doses of AZL‐M (5–80 mg) provided significant reductions in sitting clinic SBP relative to placebo from baseline to week 8 (Figure 2, Table 2). There were no statistically significant differences in the decrease in sitting SBP between any of the AZL‐M treatment groups and the OLM 20 mg reference treatment group (Figure 2, Table 2). In general, the effect of AZL‐M on sitting clinic SBP appeared to be dose‐dependent up to 40 mg (Figure 2). There were no statistically significant differences in the decrease in sitting clinic SBP between any of the AZL‐M treatment groups and the OLM 20 mg reference treatment group (Figure 2, Table 2).
Figure 2.
Changes from baseline in sitting clinic systolic blood pressure over 8 weeks. The top panel shows least squares (LS) mean change±standard error (SE) at 8 weeks (last observation carried forward). The bottom panel shows LS mean change±SE over 8 weeks (observed cases). AZL‐M indicates azilsartan medoxomil; OLM, olmesartan medoxomil. *P<.05 vs placebo. ***P<.001 vs placebo.
The results for clinic standing DBP and SBP were consistent with the sitting measurements. For DBP, the LS mean changes with AZL‐M ranged from −9.2 mm Hg (5 mg) to −11.3 mg (40 mg) compared with −6.9 mm Hg for placebo and −10.8 mm Hg for OLM 20 mg. For SBP, the LS mean changes with AZL‐M ranged from −11.4 mm Hg (5 mg) to −16.1 mm Hg (20 mg) compared with −3.3 mm Hg for placebo and −11.4 mm Hg for OLM 20 mg. Statistical comparisons between groups provided similar findings to the sitting measurements.
The results for 0 to 24‐hour ABPM measurements generally mirrored the clinic BP measurements (Figure 3, Table 2). The main differences in the clinical measurements were that LS mean changes in 0 to 24‐hour mean DBP and SBP were significantly greater with AZL‐M 40 mg vs OLM 20 mg (Figure 3, Table 2). In general, the effects of AZL‐M on DBP and SBP based on 0 to 24‐hour ABPM appeared to be dose‐dependent (Figure 3). In contrast to the clinic measurements, the placebo response using ABPM measures was small (within ±2 mm Hg) for both DBP and SBP (Table 3). Absolute changes in BP with AZL‐M based on 0 to 24‐hour ABPM tended to be smaller than those seen with clinic measurements, whereas placebo‐subtracted reductions tended to be larger. The mean ABPM results for other periods, including the daytime, nighttime, and trough values provided similar results to the entire 0 to 24‐hour period, although BP reductions tended to be greater during the trough period (Table 3).
Figure 3.
Mean 0 to 24‐hour ambulatory blood pressure monitoring (ABPM) measurements: change from baseline to final visit for diastolic blood pressures (top) and systolic blood pressure (bottom). LS indicates least squares; AZL‐M, azilsartan medoxomil. ***P<.001 vs placebo. † P<.05 vs olmesartan medoxomil (OLM).
Table 3.
Change From Baseline DBP and SBP as Measured by ABPM
| ABPM Variable | Placebo (n=43) | AZL‐M 5 mg (n=56) | AZL‐M 10 mg (n=45) | AZL‐M 20 mg (n=47) | AZL‐M 40 mg (n=41) | AZL‐M 80 mg (n=45) | OLM 20 mg (n=50) |
|---|---|---|---|---|---|---|---|
| Mean 24‐h DBP | 1.2±1.0 | −4.2±0.9a | −7.3±1.0a | −7.5±1.0a | −9.6±1.1a , b | −8.2±1.0a | −6.2±1.0a |
| Mean daytime DBP while awake | 0.7±1.1 | −4.2±1.0a | −7.7±1.1a | −8.0±1.1a | −10.6±1.1a , c | −8.7±1.1a | −6.0±1.0a |
| Mean nighttime DBP while asleep | 1.9±1.3 | −4.8±1.1a | −7.4±1.2a | −6.8±1.2a | −8.5±1.3a | −7.8±1.2a | −6.1±1.2a |
| Mean trough DBP | −0.3±1.5 | −7.6±1.3a | −11.3±1.4a | −8.9±1.4a | −14.0±1.5a , b | −9.0±1.4a | −9.6±1.3a |
| Mean 24‐h SBP | 1.0±1.5 | −7.5±1.3a | −12.1±1.5a | −11.1±1.5a | −15.8±1.6a , c | −12.4±1.5a | −9.3±1.4a |
| Mean daytime SBP while awake | 0.7±1.6 | −7.8±1.4a | −13.0±1.6a , b | −11.6±1.6a | −17.3±1.7a , d | −13.1±1.6a , b | −8.6±1.5a |
| Mean nighttime SBP while asleep | 1.3±1.8 | −7.3±1.6a | −11.1±1.7a | −10.4±1.7a | −13.1±1.8a | −11.4±1.7a | −10.6±1.6a |
| Mean trough SBP | −1.5±2.1 | −10.9±1.8a | −14.9±2.0a | −12.0±1.9a | −18.8±2.1a | −13.9±2.0a | −13.8±1.9a |
Abbreviations: AZL‐M, azilsartan medoxomil; DBP, diastolic blood pressure; SBP, systolic blood pressure. All data are expressed as least squares mean±standard error (mm Hg) at week 8. n given are the number of patients with ambulatory blood pressure monitoring (ABPM) at baseline and at the end of the study. a P<.001 vs placebo. b P<.05 vs olmesartan medoxomil (OLM). c P<.01 vs OLM. d P<.001 vs OLM.
Safety and Tolerability
A total of 157 of 445 patients (35%) experienced at least one AE during the study (Table 4). The overall incidence of AEs in the AZL‐M treatment groups was not dose‐dependent or different from placebo or OLM. The most common AE was headache (reported by 3.1%–10.9% of patients across the different treatment groups). Other AEs occurring in ≥5% of patients in any treatment group were nasopharyngitis, dizziness, and upper respiratory infection. Nine patients (2.0%) discontinued the study because of AEs, including two in the placebo group (n=1 with a gastrointestinal hemorrhage; n=1 with increased BP), two in the AZL‐M 80 mg (both with hypotension), two in the OLM 20 mg (n=1 with a cardiac arrest, n=1 with dysuria and testicular pain), and one in each in the AZL‐M 10 mg (hydrocephalus), 20 mg (urticaria), and 40 mg (esophageal spasm) treatment groups. Serious AEs were reported in five patients: one in each of the placebo, AZL‐M 5 mg, 10 mg, 40 mg, and OLM 20 mg treatment groups. This included one death caused by cardiac arrest in the OLM 20 mg group. None of the serious AEs were considered to be related to the study drug by the investigator. There were no notable changes in laboratory parameters (including alanine aminotransferase, aspartate aminotransferase, hemoglobin, potassium, creatinine), physical examination, vital signs, or 12‐lead electrocardiography results in any of the treatment groups.
Table 4.
Overview of AEs (Safety Population)
| Event | Placebo (n=63) | AZL‐M 5 mg (n=65) | AZL‐M 10 mg (n=64) | AZL‐M 20 mg (n=64) | AZL‐M 40 mg (n=62) | AZL‐M 80 mg (n=64) | OLM 20 mg (n=63) |
|---|---|---|---|---|---|---|---|
| Death | 0 | 0 | 0 | 0 | 0 | 0 | 1 (1.6) |
| Serious AE | 1 (1.6) | 1 (1.5) | 1 (1.6) | 0 | 1 (1.6) | 0 | 1 (1.6) |
| Any AE | 26 (41.3) | 23 (35.4) | 22 (34.4) | 23 (35.9) | 20 (32.3) | 22 (34.4) | 21 (33.3) |
| Mild | 12 (19.0) | 16 (24.6) | 12 (18.8) | 13 (20.3) | 8 (12.9) | 12 (18.8) | 12 (19.0) |
| Moderate | 13 (20.6) | 7 (10.8) | 10 (15.6) | 10 (15.6) | 12 (19.4) | 9 (14.1) | 7 (11.1) |
| Severe | 1 (1.6) | 0 | 0 | 0 | 0 | 1 (1.6) | 2 (3.2) |
| Leading to discontinuationa | 2 (3.2) | 0 | 1 (1.6) | 1 (1.6) | 1 (1.6) | 2 (3.1) | 2 (3.2) |
| AE (preferred term) in ≥5% of patients in any group | |||||||
| Headache | 3 (4.8) | 2 (3.1) | 2 (3.1) | 7 (10.9) | 3 (4.8) | 3 (4.7) | 5 (7.9) |
| Nasopharyngitis | 4 (6.3) | 0 | 3 (4.7) | 3 (4.7) | 1 (1.6) | 3 (4.7) | 1 (1.6) |
| Dizziness | 2 (3.2) | 1 (1.5) | 3 (4.7) | 4 (6.3) | 2 (3.2) | 1 (1.6) | 1 (1.6) |
| Upper respiratory tract infection | 0 | 4 (6.2) | 0 | 0 | 2 (3.2) | 0 | 0 |
Abbreviations: AE, adverse event; AZL‐M, azilsartan medoxomil; OLM, olmesartan medoxomil. Values are expressed as number (percentage).
Temporary drug interruption or permanent discontinuation.
Discussion
The current study demonstrated that the capsule formulation of AZL‐M administered once daily provided rapid, statistically significant, and clinically relevant reductions in DBP and SBP relative to placebo at all doses tested from 5 to 80 mg (with the exception of 5 mg for clinic DBP) in patients with mild to moderate uncomplicated essential hypertension. Changes in clinic DBP and SBP with AZL‐M at all doses were generally statistically indistinguishable from those provided by OLM 20 mg. However, there was some evidence of greater reductions in DBP and SBP with the 40 mg AZL‐M dose vs OLM 20 mg based on 24‐hour ABPM measurements. Several subsequent phase 3 studies with AZL‐M have used ABPM measurements rather than clinic BP measurements for the primary analyses,24, 25, 26 and this may represent a more reliable parameter, as it is only minimally affected by placebo (as confirmed in the current study) and is better for predicting long‐term outcomes.27, 28, 29, 30 As a result of the lack of placebo effect, ABPM is more likely to detect masked hypertension and avoid white‐coat hypertension.29, 30
Although there was some evidence of a dose‐response relationship for AZL‐M in the current study, this may have been masked somewhat by the variability associated with the effect of food (see below). Shallow dose‐response relationships for BP lowering appear to be typical for ARB drugs, especially in standard dose‐ranging studies where drug doses are not titrated.31 However, in more clinically relevant settings, such as dose‐titration studies or in clinical practice itself (where dose is driven by BP response and tolerability), steeper relationships are apparent.31
It should be emphasized that the AZL‐M capsule formulation used in the current study differs from the commercially approved formulation, which is an AZL‐M prodrug tablet. Previous studies have shown that systemic AZL exposure with the AZL‐M capsule is approximately 40% lower than that provided by the AZL‐M tablet when administered in the fasting state.23 Furthermore, when administered in the fed state, the capsule has a pronounced food effect that results in higher, but more variable, plasma exposure to AZL (the commercial tablet formulation, on the other hand, is not significantly affected by food).23 In the current study, patients were encouraged to administer study treatment with food. Although the effect of dosing with food in the current study may have offset the lower bioavailability of the capsule formulation to some extent, it could also have imparted more variability in AZL exposure.23 Thus, the suboptimal properties of the AZL‐M prodrug capsule formulation may have contributed to both reduced efficacy and increased variability in this trial. Indeed, in subsequent phase 3 studies using the improved AZL‐M prodrug tablet formulation, AZL‐M 80 mg once daily was shown to provide statistically superior 24‐hour ambulatory and clinic BP reductions compared with OLM 40 mg, while the AZL‐M 40 mg dose was noninferior.24, 25, 26 Significantly greater BP reductions with both AZL‐M 40 mg and 80 mg were also seen compared with valsartan 320 mg.25, 26
A similar 8‐week phase 2 dose‐ranging study also performed in the United States and Latin America used an AZL (rather than AZL‐M prodrug) tablet formulation over a dose range 2.5 to 40 mg once daily.23 Notably, that study demonstrated less variability in BP‐lowering response and clearer (but shallow) dose‐proportionality compared with the current study. However, absolute and placebo‐subtracted DBP and SBP reductions were generally very similar in magnitude to those reported in the current study (and statistically significant for AZL vs placebo at all doses, except for DBP at 2.5 mg). Furthermore, unlike in the current study, reductions in clinic BP were statistically superior compared with OLM 20 mg at the higher doses of AZL (40 mg for DBP, 20 and 40 mg for SBP). The superiority demonstrated for the 40 mg dose of the AZL tablet vs OLM 20 mg provided the justification for investigating the 80 mg dose of the AZL‐M tablet (with its more favorable characteristics over the capsule) in phase 3 studies. The results from those studies confirmed the superior BP‐lowering efficacy of AZL‐M 80 mg over the maximum approved doses of OLM 40 mg or valsartan 320 mg (the maximum approved doses in the United States) and AZL‐M 80 mg became the recommended dose in the United States.12, 24, 25, 26, 32, 33 The tablet formulation of AZL (rather than AZL‐M) has been commercially developed in Japan, and in a head‐to‐head phase 3 study in Japanese patients with hypertension, AZL 40 mg once daily provided a statistically superior reduction in DBP and SBP compared with candesartan cilexetil 12 mg once daily (the maximum approved dose in Japan).34
The full range of doses selected for this study was determined to be safe and well tolerated in previous phase 1 and 2 clinical studies and this was also the case in the current study. The safety profile of AZL‐M observed in the current study was similar to placebo and the comparator ARB OLM 20 mg. The overall incidence of AEs was not dose‐dependent and all doses were well tolerated. Serious AEs were distributed across the AZL‐M treatment groups and were not considered related to the study drug. The safety profile reported for AZL‐M in the current study is consistent with previous data for other ARBs and was confirmed in subsequent phase 3 studies.4, 8, 9, 24, 25, 26
Conclusions
The results of this study showed that AZL‐M has potent antihypertensive effects and a good tolerability profile in patients with mild to moderate uncomplicated essential hypertension. Treatment with AZL‐M (capsule formulation) at doses ranging from 10 to 80 mg resulted in significant, rapid reductions in clinic DBP and SBP. In general, AZL‐M 40 mg had the most consistent treatment effect and was more effective than OLM 20 mg based on ABPM measurements. Along with the other phase 2 dose‐range study (using a tablet formulation of AZL), these findings provided the basis for subsequent phase 3 trials using the commercial AZL‐M tablet in the dose range of 20 to 80 mg per day.
Supporting information
Figure S1. CONSORT flow diagram.
Acknowledgments and Disclosures
AP is retired but was an employee of Takeda, the company that sponsored the study, during the time the research was conducted. CC is a full‐time employee of Takeda. Medical writing assistance was funded by Takeda and was provided by Absolute Healthcare Communications Ltd, Twickenham, United Kingdom.
J Clin Hypertens (Greenwich). 2017;19:312–321. 10.1111/jch.12895 © 2016. Wiley Periodicals, Inc.
Alfonso Perez is retired but was an employee of Takeda during the time of the research.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. CONSORT flow diagram.