Demographics and baseline characteristics

A total of 122 patients were randomized into 4 groups (Supplementary Fig. 1), of which 121 patients were included in the FAS, including 30 patients in each subgroup of the 3 different dosage regimens of SPH3127 tablet and 31 patients in the placebo group. Demographics and baseline characteristics were well balanced in the 4 groups (Table 1). A total of 108 patients were included in the PPS, including 26 patients in the SPH3127 50-mg group, 24 patients in the 100-mg group, 27 patients in the 200-mg group, and 31 patients in the placebo group (Supplementary Fig. 1).

Table 1 Demographic and baseline characteristics

All patients were reconfirmed to have mild or moderate essential hypertension before randomization. The previous antihypertensive medications were roughly proportional in the 4 groups: 10 (31.3%) patients in the placebo group, 12 (40.0%) patients in the 50-mg group, 13 (43.3%) patients in the 100-mg group, and 17 (56.7%) patients in the 200-mg group.

EfficacyPrimary endpoints msDBP

In the FAS, after 8 weeks of treatment, the msDBP was unanimously decreased from the baseline by 5.7 ± 9.5, 8.6 ± 8.8, and 3.8 ± 10.6 mmHg in the SPH3127 50-, 100-, and 200-mg groups, respectively, and 3.1 ± 8.4 mmHg in the placebo group.

In the PPS, after 8 weeks of treatment, the msDBP decreased by 5.6 ± 10.2, 10.0 ± 9.2, and 4.0 ± 10.2 mmHg in the SPH3127 50-, 100-, and 200-mg groups, respectively, and 3.1 ± 8.4 mmHg in the placebo group.

The sensitive analysis of the PPS also suggested that the 100-mg dosage was associated with the greatest reductions in msDBP; on the other hand, placebo was associated with the smallest reduction (Table 2).

Table 2 Changes in msDBP from baseline to 8 weeks of treatment msSBP

In the FAS, after 8 weeks of treatment, the msSBP decreased from baseline by 11.8 ± 13.0, 13.8 ± 11.2, and 11.1 ± 13.1 mmHg in the SPH3127 50-, 100-, and 200-mg groups, respectively, and 7.7 ± 9.7 mmHg in the placebo group.

In the PPS, after 8 weeks of treatment, the msSBP decreased from baseline by 12.2 ± 13.8, 16.2 ± 10.8, and 12.3 ± 11.9 mmHg in the SPH3127 50-, 100-, and 200-mg groups, respectively, and 7.7 ± 9.7 mmHg in the placebo group.

The reductions in msSBP were greater in the SPH3127 100-mg group compared with other dosage groups and placebo group, whereas similar reductions were reported with 50- and 200-mg dosages (Table 3).

Table 3 Changes in msSBP from baseline to 8 weeks of treatment

From the primary analysis, SPH3127 tablet is efficacious to decrease the msDBP and msSBP after 8 weeks of treatment with each dosage regimen compared with placebo. Moreover, the reductions in BP were greater in the SPH3127 100-mg group compared with other dosage groups and placebo group.

Secondary end points Changes in msDBP and msSBP from baseline to 2, 4, and 6 weeks of treatment

The changes in the msDBP and msSBP from baseline to 2, 4, and 6 weeks of treatment showed a similar trend of decrease in the SPH3127 dosage groups, and the decrease was greater compared with that in the placebo group (Supplementary Fig. 1 and Fig. 2). In particular, in the SPH3127 100-mg group, the biweekly measurements clearly showed that the mean reductions in msBP were evident by week 2, with further reductions at week 6, exhibiting the most obvious downward trend of both msSBP and msDBP over time (Fig. 2).

Fig. 2

Changes in msDBP and msSBP during the consecutive follow-ups. msDBP mean sitting diastolic blood pressure, msSBP mean sitting systolic blood pressure

Changes in 24-h ambulatory BP after 8 weeks of treatment

After 8 weeks of treatment, the changes in the 24-hour ambulatory msDBP were 1.15, 4.19, 3.86, and 4.70 mmHg and the changes in msSBP were 0.06, 5.15, 7.32, and 15.38 mmHg in the placebo and SPH3127 50-, 100-, as well as 200-mg groups, respectively. Generally, the decrease in 24-hour ambulatory BP was most evident in the 100-mg group, although all the 3 dosages reduced either msDBP or msSBP in varying degrees (Supplementary Fig. 2).

Response rate and control rate after 4 and 8 weeks of treatment

Both total response rate and control rate in the 3 SPH3127 dosage groups were all higher than those in the placebo group after 4 and 8 weeks of treatment, whereas the most remarkable efficacy was reported in the 100-mg group (Supplementary Table 1).

Changes in PRA from baseline after 4 and 8 weeks of treatment

The most significant decrease in PRA was reported in the SPH3127 100-mg group after 8 weeks of treatment, and both the 100- and 200-mg groups were reported with a decrease in PRA from baseline after 4 and 8 weeks of treatment, whereas no significant change was observed in the placebo group (Supplementary Fig. 3).

Safety analysis

In the SS of 122 patients, AEs were reported by 17 (56.67%), 22 (73.33%), 23 (76.67%), and 26 (81.25%) patients in the SPH3127 50-, 100-, and 200-mg tablet and placebo groups, respectively, and the total number of AEs reported was 52, 73, 61, and 85 in each group, respectively (Table 4).

Table 4 Safety analysis of 3 dosage regimens of SPH3127 versus placebo

Most of AEs were grades 1 to 2 in severity, and AEs of grade 3 or more were reported by 2 (6.67%), 1 (3.33%), 1 (3.33%) and 1 (3.13%) patients in SPH3127 50-, 100-, and 200-mg and the placebo groups, respectively. Two AEs of liver injury and hypertension in the 50-mg group led to dosing discontinuation. One AE of aggravated hypertension was observed in the 200-mg group leading to the discontinuation. However, with respect to these important AEs, no significant differences were observed in the 4 groups. In addition, all the important AEs were manageable, being curative after discontinuation of interventions, and no sequelae was reported during the follow-up.

Probability of AEs associated with SPH3127 were reported in 3 (10%) patients with 3 AEs in the 50-mg group, 6 (20%) patients with 9 AEs in the 100-mg group, 7 (23.3%) patients with 9 AEs in the 200-mg group and 5 (15.63%) patients with 6 AEs in the placebo group. Most AEs were abnormal laboratory values and recovered without any intervention (Table 4).