A phase 3 double-blind randomized (CONSORT-compliant) study of azilsartan medoxomil compared to valsartan in Chinese patients with essential hypertension

Abstract

Background: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has a well-characterized efficacy and safety profile in patients with hypertension. AZL-M is approved for use in over 40 countries globally; however, it is not yet approved in China. Therefore, a phase 3 registration study to assess the efficacy (antihypertensive effect), safety, and tolerability of AZL-M compared with valsartan in Chinese patients with essential hypertension was undertaken.

Methods: This multicenter, double-blind, randomized, 8-week phase 3 study compared AZL-M with valsartan in Chinese patients aged ≥18 years with essential hypertension. Endpoints included change from baseline to week 8 in trough sitting clinic systolic blood pressure (scSBP) and ambulatory blood pressure monitoring parameters.

Results: Overall, 612 patients (mean age, 57.1 years; 57.5% male) were randomized to AZL-M 80 mg (n = 209), AZL-M 40 mg (n = 199), or valsartan 160 mg (n = 204). Baseline mean scSBP was similar in all groups (157.9-158.5 mm Hg). The mean reduction in trough scSBP from baseline to week 8 was significantly greater with AZL-M 80 mg than with valsartan (-24.2 vs -20.6 mm Hg; P = .010), and noninferior with AZL-M 40 mg versus valsartan (-22.5 vs -20.6 mm Hg; P = .184). Mean reduction in 24-hour mean systolic blood pressure (n = 257) was significantly greater with both AZL-M 80 mg (-17.0 mm Hg; P < .001) and AZL-M 40 mg (-14.7 mm Hg; P = .014) than with valsartan (-9.4 mm Hg). Treatment-emergent adverse events had similar incidence (52.8%-56.5%) across the treatment groups and were generally mild or moderate. Dizziness was the most frequent treatment-related treatment-emergent adverse events (AZL-M 80 mg, 1.9%; AZL-M 40 mg, 1.5%; valsartan, 1.0%). The safety and tolerability of AZL-M were comparable with valsartan.

Conclusions: AZL-M was noninferior to valsartan at the 40-mg dose and superior to valsartan at the 80-mg dose in reducing trough scSBP, and showed acceptable safety-consistent with the AZL-M safety profile in other populations-in Chinese adults with hypertension.

Trial registration number: NCT02480764.

Conflict of interest statement

Jingtao Wu is an employee of Takeda. Michie Hisada and Wei Zhou are former employees of Takeda. The other authors have no conflicts of interest to disclose.

Figures

Figure 1

Study design. ∗The screening visit was scheduled before the washout/run-in period so that laboratory tests results were reviewed and patient eligibility confirmed before other treatments were stopped or placebo was initiated. †Patients were notified by telephone to begin the washout period. ‡Patients taking previous antihypertensive agents were required to participate in a 3-week washout/run-in period (days −21–−1). §If the subject's previous antihypertensive treatment included amlodipine or chlorthalidone, the washout was extended to 4 weeks (days −28–−1). ‖The first dose of placebo was taken at the clinic on day −14 (visit 2). ∗∗Patients who had not received antihypertensive treatment within 28 days before screening were entered into the run-in period as soon as all inclusion and exclusion criteria, including laboratory results, were verified. ††The last dose of double-blind treatment was the day of week 8/final clinic visit or ET (visit 9); patients in the ABPM subgroup started 24-hour ABPM measurement. ‡‡The follow-up telephone contact was made approximately 14 days after the last dose. §§Visit 4 applied to ABPM subgroup patients only, who started 24-hour ABPM measurement. ‖‖Visit 10 applied to ABPM subgroup patients only. ABPM = ambulatory blood pressure monitoring. AZL-M = azilsartan medoxomil, D = day, ET = early termination, N/A = not applicable, QD = once daily.

Figure 2

Consort flow diagram. ∗Patients who completed the study were the total number randomized per treatment group minus those who discontinued. †Patients could have had more than 1 reason for discontinuation; only the primary reason is presented. AE = adverse event, AZL-M = azilsartan medoxomil, PTE = pretreatment event.

Figure 3

Least squares mean (standard error) change from baseline to week 8 in trough sitting clinic systolic blood pressure and sitting clinic diastolic blood pressure (full analysis set, last observation carried forward). ∗Indicates P≤.01 compared with valsartan 160 mg. +Values in parentheses are the least squares mean difference between azilsartan medoxomil and valsartan. FAS = full analysis set, LOCF = last observation carried forward, LS = least squares, scDBP = sitting clinic diastolic blood pressure, scSBP = sitting clinic systolic blood pressure, SE = standard error.

Figure 4

Change from baseline in trough sitting clinic systolic blood pressure and sitting clinic diastolic blood pressure at weeks 2, 4, 6, and 8 (full analysis set, last observation carried forward). ∗P < .05. ∗∗P≤.01. ∗∗∗P≤.001. FAS = full analysis set, LOCF = last observation carried forward, scDBP = sitting clinic diastolic blood pressure, scSBP = sitting clinic blood pressure.

Figure 5

Hourly systolic blood pressure (A) and diastolic blood pressure (B) ambulatory blood pressure monitoring data at week 8. ABPM = ambulatory blood pressure monitoring, AZL-M = azilsartan medoxomil, DBP = diastolic blood pressure, LS = least squares, SBP = systolic blood pressure, SE = standard error.