SPH3127 Phase III Trial Reports Noninferior Blood Pressure Lowering

Key Takeaways

• SPH3127 100 mg once daily was associated with week 12 blood pressure lowering that was noninferior to valsartan on the prespecified primary endpoint.
• Stage 1 supported carrying forward the 100 mg dose after it showed the largest week 12 mean sitting diastolic blood pressure reduction and high plasma renin activity inhibition.
• Safety outcomes were broadly similar, serious adverse drug reactions were not observed, and week 12 mean sitting diastolic blood pressure reductions were comparable across age, sex, and baseline mean sitting diastolic blood pressure strata.

In a phase III randomized trial of SPH3127, adults with mild-to-moderate essential hypertension had week 12 mean sitting diastolic blood pressure lowering that met the prespecified noninferiority criterion versus valsartan 80 mg.

The multicenter, randomized, double-blind, double-dummy, positive-drug-controlled phase III study used a 2-stage design in China. Stage 1 compared SPH3127 50 mg, 100 mg, and 200 mg once daily with valsartan 80 mg once daily for 12 weeks, while stage 2 compared SPH3127 100 mg once daily with valsartan 80 mg once daily for 12 weeks. The prespecified primary endpoint was change from baseline in mean sitting diastolic blood pressure at week 12. In stage 1, week 12 mean sitting diastolic blood pressure changed by −4.76 ± 6.47 mmHg, −8.17 ± 5.90 mmHg, and −6.39 ± 8.64 mmHg with SPH3127 50, 100, and 200 mg, versus −6.23 ± 6.41 mmHg with valsartan. Plasma renin activity inhibition reached 83% with 100 mg and 89% with 200 mg, and 100 mg moved into the confirmatory stage.

Stage 2 randomized 828 patients, assigning 413 to SPH3127 and 415 to valsartan. In the treatment-policy analysis, least-square mean change from baseline in mean sitting diastolic blood pressure at week 12 was 5.97 mmHg with SPH3127 and 6.32 mmHg with valsartan, for a between-group difference of −0.35 mmHg with a 95% CI of −1.48 to 0.78 and p=0.005 in the noninferiority comparison with valsartan. The prespecified margin was −1.83 mmHg. A supporting hypothetical strategy showed corresponding least-square mean values of 5.95 mmHg and 6.31 mmHg, with a difference of −0.36 mmHg, a 95% CI of −1.51 to 0.78, and p=0.006. The primary endpoint result was consistent between the main and sensitivity analyses.

Short-term safety findings were broadly similar over 12 weeks, with treatment-emergent adverse events in 61.1% of SPH3127 patients and 56.2% of valsartan patients. Adverse drug reactions occurred in 8.3% and 10.0%, respectively, and no serious adverse drug reactions or CTCAE grade 3 or higher adverse drug reactions were reported. Serious adverse events occurred in 10 patients and were considered unrelated to study drugs, while hyperkalemia adverse drug reactions were reported in one SPH3127 patient and two valsartan patients. No adverse drug reaction led to treatment withdrawal in the SPH3127 group, whereas one valsartan patient withdrew because of abnormal liver function test results considered related to valsartan.

Across age, sex, and baseline mean sitting diastolic blood pressure strata below or at least 100 mmHg, week 12 mean sitting diastolic blood pressure reduction was comparable, although the randomized comparisons were limited to Chinese patients and 12-week treatment periods. Long-term safety observation in stage 2 was ongoing at publication, and SPH3127 100 mg once daily was effective and safe for adults with mild-to-moderate essential hypertension within the reported setting.