China Stroke Primary Prevention Trial 2 for Participants With Hypertension and MTHFR 677 TT Genotype

This study consists of 3 periods: Screening, Run-in, and Randomized treatment. Period I: Screening (V0) The purpose of Period I is to obtain informed consent and screen for eligible participants. After obtaining written informed consent, at the screening visit (V0), participants will complete a face-to-face interview and clinical evaluation and measurements. Their biological samples will be collected for laboratory analyses. Collectively, these information will help to determine eligibility for inclusion in the study. Period II: Run-in Period (VD) The purpose of Run-in is to assess participants' compliance for following the amlodipine treatment regimen as well as to observe participants' tolerance to amlodipine, so as to screen out those with poor compliance or intolerance to amlodipine treatment. The run-in phase lasted 2 to 4 weeks, during which oral administration of Amlodipine tablets (5 mg) was given once daily. Period III: Randomized Treatment (V1-V21) This is a 5-year period of randomized, double-blind, triple-dummy, controlled treatment. At each of the research centers, participants who remain eligible for participation in the study will be randomized into 3 treatment groups: A. Amlodipine-only (5mg/d) with an amlodipine folic acid placebo and 5-MTHF placebos. B. Amlodipine folic acid tablet (5.8mg/d) with amlodipine placebo and 5-MTHF placebo. C. Amlodipine folic acid tablets (5.8mg/d) and 5-MTHF (0.4mg/d) with an amlodipine placebo in a 1:1:1 ratio, using the randomization and trial supply management (RTSM) platform. During the treatment period, other antihypertensive drugs can be added to achieve blood pressure control (BP ≤140/90mmHg), including Valsartan (80mg/d), or/and Indapamide (1.5mg/d), or/and metoprolol tartrate tablets (25mg/d). Participants will be followed up every 3 months during the treatment period, and the treatment drugs will be distributed at each visit. A total of 24,000 participants will be randomly assigned to one of three treatment groups (Group A n=8,000, Group B n=8,000, Group C n=8,000). Based on published data from CSPPT (Huo et al, JAMA, 2015), the 5-year cumulative incidence of first ischemic stroke in the amlodipine-only group is 3.5%. Assuming the 5-year cumulative incidence of first ischemic stroke in the amlodipine-only group is around 3.5%, this trial has 80% power to detect a 20% difference between group A and group B+C in the observed hazard ratio (HR) for incident ischemic stroke (HR≤0.80), at a two-sided significance level of α=0.05. If instead, the 5-year incidence of ischemic stroke in the amlodipine-only group is 2.5%, this trial has 80% power to detect a 23% difference between the treatment groups (A vs B+C) (HR≤0.77). There are two planned interim analyses, one at the end of the third year, and another at the end of the fourth year. The O'Brien-Fleming alpha-spending function will be used to define the significance level of each interim analysis to ensure that the final overall two-sided significance level of α=0.05 is met.