Multicenter, Randomized, Double-Blind, Parallel, Phase 2 Clinical Trial to Compare and Evaluate the Efficacy and Safety of SPC1001 and Monotherapy in Patients With Essential Hypertension

Abstract

Purpose: Hypertension poses challenges for many patients in achieving adequate blood pressure control, despite using monotherapy or standard treatment regimens. A low-dose triple combination drug has recently been considered for initial hypertension therapy; however, its safety, efficacy, and dose-response relationship remain unclear. We evaluated these aspects for patients with hypertension to determine the optimal combination dose. Methods: A multicenter, randomized, double-blind, parallel, phase 2 clinical trial was conducted in South Korea. Following a two-week placebo run-in period, 253 patients of SPC1001 were randomized into the High, Mid1, Mid2, and Low groups, which consisted of a fixed-dose triple combination of candesartan, amlodipine, and indapamide at varying doses. The dosages were SPC1001 High (4/2.5/1.25 mg), SPC1001 Mid1 (2.67/1.67/0.83 mg), SPC1001 Mid2 (4/1.25/1.25 mg), SPC1001 Low (2/1.25/0.625 mg), SPC3001 (candesartan 8 mg), SPC4001 (amlodipine 5 mg), SPC4002 (amlodipine 10 mg), and placebo, with the number of participants in the groups at a 1:1:1:1:1:1:1:1 ratio. Participants who had been using antihypertensive medication during the screening visit were required to discontinue it at least 4 weeks before the run-in period. The primary endpoint was determined by evaluating how mean sitting systolic blood pressure (MSSBP) varied between the baseline measurement and week 8. Treatment emergent adverse events and clinically significant changes on physical examination, including the assessment of ankle edema, laboratory tests, vital signs, and 12-lead electrocardiography, were also evaluated. Findings: SPC1001 High and SPC1001 Mid2 were identified as the two groups with the most effective dosages. The least square mean difference (LSMD) of SPC1001 High compared to SPC3001, SPC4001, SPC4002, and placebo was –7.50, −7.68, 0.03, and −16.97 mm Hg, respectively (P-values for ANCOVA were 0.04, 0.0473, 0.9929, and <0.0001). The LSMD of SPC 1001 Mid2 compared with that of SPC3001, SPC4001, SPC4002, and placebo was −8.72, −8.72, −1.85, and −18.02 mm Hg, respectively (P-values for ANCOVA were 0.0075, 0.0119, 0.5704, and <0.0001). The LSMD of SPC 1001 Mid1 compared to that of SPC3001, SPC4001, SPC4002, and placebo was −4.90, −5.21, 3.03, and −14.44 mm Hg, respectively (P-values for ANCOVA were 0.1178, 0.1205, 0.3347, and <0.0001). The LSMD of SPC1001 Low compared to that of SPC3001, SPC4001, SPC4002, and placebo was −0.51, −0.87, 7.30, and −9.88 mm Hg, respectively (P-values for ANCOVA were 0.8799, 0.8088, 0.0284, and <0.0047). There were two serious adverse events recorded, in SPC1001 High and SPC3001. Implications: Low-dose triple combination therapies may be effective for treating hypertension.