Efficacy and safety of low-dose antihypertensive combination drugs including amlodipine, telmisartan, and chlorthalidone: a multicenter, randomized, double-blinded, parallel, phase III clinical trial

Abstract Background AD-209 is a low-dose combination of telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (6.25 mg). A high-dose combination of these three components has already been developed and is available in the South Korea’s market. Given the established efficacy and safety profile of the higher dose and the parallel development of AD-209 at half the dose, safety concerns are not anticipated. This study evaluates the efficacy and safety of a low-dose combination of telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (6.25 mg), compared to telmisartan (40 mg) alone. Purpose This study assesses the effectiveness and safety of AD-209, a combination of telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (6.25 mg), in patients with essential hypertension. The gatekeeping method was used to test the Part 1 non-inferiority hypothesis, followed by the Part 2 superiority hypothesis. Methods This randomised, double-blind, parallel, multicentre, Phase III trial enrolled 314 patients, randomly assigned (1:1) to the test group (AD-209; telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 6.25 mg) and the control group (telmisartan 40 mg) at 28 sites in South Korea to receive the investigational product for 8 weeks. The efficacy and safety were assessed at 4 and 8 weeks after randomisation. Results The primary efficacy endpoint, defined as the change in the mean sitting systolic blood pressure (MSSBP) from baseline to 8 weeks in patients with mild-to-moderate hypertension, was -19.43 mmHg in the test group and -15.65 mmHg in the control group. The non-inferiority test showed that the LS mean difference between the test and control groups was -3.78 mmHg (95% CI: -6.67, -0.89), with the upper limit of the 95% confidence interval (-0.89) being less than the prespecified non-inferiority limit (NI margin = 3 mmHg), indicating non-inferiority of the test group compared to the control group. The superiority test demonstrated a mean difference of -19.17 mmHg in the test group and -15.16 mmHg in the control group. The LS mean difference between the test and control groups was -4.01 mmHg (p = 0.0046), indicating the efficacy of the test group in comparison to the control group. Regarding safety, 31 treatment-emergent adverse events (TEAEs) were documented in 26 of the 312 patients (8.33%) in the safety set, including two cases of adverse drug reactions (ADRs) in two patients (0.64%). The difference in the occurrence of TEAEs and ADRs was not statistically significant between the test and control groups. Conclusions In conclusion, this study suggests that AD-209, a low-dose combination of telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (6.25 mg) provides a significant blood pressure-lowering effect compared to telmisartan (40 mg), in patients with essential hypertension, with a similar safety profile.