This is a multi-center, randomized, double-blind, double-dummy, controlled clinical trial. This trial will include 32,000 Chinese men and women with hypertension (H-type hypertension), MTHFR 677 CC or CT genotype, elevated plasma total homocysteine (tHcy ≥10µmol/L), and insufficient serum folate levels (\<12ng/mL). The participants will be first stratified by their MTHFR 677 genotype (CC vs. CT), then randomized to one of two treatment groups in a 1:1 ratio. Group A: amlodipine tablet (5mg), taken orally, once daily, serving as active comparator. Group B: amlodipine folic acid 5.8mg tablet (5mg amlodipine and 0.8mg folic acid), taken orally, once daily. The treatment period is five years and primary endpoint is first ischemic stroke.
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 first 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 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 randomized, double-blind, double-dummy, controlled treatment with a total of 5-years. At each of the participating centers, participants who remain eligible for participation at V1 will first be stratified by MTHFR genotypes: CC vs. CT. Within each genotype stratum, participants will then be randomized into 2 treatment groups: either an amlodipine-only tablet (5mg/d) with a dummy tablet or an amlodipine folic acid tablet (5.8mg/d) with a dummy tablet in a 1:1 ratio, using randomization and trial supply management (RTSM) platform. During the treatment period, other antihypertensive drugs can be added to achieve the target 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 every 3 months during the five-year treatment period, and the treatment drugs will be distributed at each visit. A total of 32,000 participants will be randomly assigned to one of the two treatment groups: Group A: amlodipine 5.0mg (n=16,000) and Group B: amlodipine-folic acid 5.8mg (n=16,000). Based on published data from CSPPT (Huo et al, JAMA, 2015), the 5-year cumulative incidence of ischemic stroke is around 2.9%. Assuming the 5-year cumulative incidence of ischemic stroke is 2.5% in the amlodipine-only group, this trial has 80% power to detect a 20% difference between group A and group B 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 cumulative incidence of ischemic stroke in the amlodipine-only group is 3.5%, this trial has 80% power to detect a 16% difference between group A and group B (HR ≤0.84). 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
32,000
The amlodipine used in this study is a listed product. Amlodipine tablets and amlodipine folic acid (dummy) are provided in aluminum-plastic blisters packaging. Each package includes 100 days of treatment drug (including 10 extra days of treatment for the follow-up window). A package of medication consists of 20 plates, each plate includes a total of 10 tablets arranged as follows: amlodipine 5mg/tablet x5 tablets + amlodipine-folic acid (dummy) x5 tablets. Affixed to the medication package is the randomized treatment drug label (200 tablets/package, 2 tablets/day).
The amlodipine besylate and folic acid tablets have been approved for listing by the China Food and Drug Administration, approval number: Zhunzi H20180020. Amlodipine-folic acid tablets and amlodipine (dummy) are provided in aluminum-plastic blisters packaging. Each package includes 100 days of treatment drug (including 10 extra days of treatment for the follow-up window). A package of medication consists of 20 plates, each plate includes a total of 10 tablets arranged as follows: amlodipine-folic acid 5.8mg x5 tablets + amlodipine (dummy) x5 tablets. Affixed to the medication package is the randomized treatment drug label (200 tablets/package, 2 tablets/day).
An amlodipine placebo is a dummy pill of an amlodipine tablet with an identical appearance.
An Amlodipine folic acid placebo is a dummy pill of an amlodipine folic acid tablet with an identical appearance.
First Affiliated Hospital of Bengbu Medical University
Bengbu, Anhui, China
NOT_YET_RECRUITINGBozhou
Bozhou, Anhui, China
NOT_YET_RECRUITINGChizhou People's Hospital
Chizhou, Anhui, China
NOT_YET_RECRUITINGTaihe County People's Hospital
Fuyang, Anhui, China
NOT_YET_RECRUITINGPeking University First Hospital
Beijing, Beijing Municipality, China
NOT_YET_RECRUITINGYangjiang People's Hospital
Yangjiang, Guangdong, China
NOT_YET_RECRUITINGThe Affiliated Hospital Of Guizhou Medical University
Guiyang, Guizhou, China
NOT_YET_RECRUITINGThe First Affiliated Hospital of Hunan University of Medicine
Huaihua, Hunan, China
NOT_YET_RECRUITINGLoudi Central Hospital
Loudi, Hunan, China
NOT_YET_RECRUITINGLianyungang Oriental Hospital
Lianyungang, Jiangsu, China
RECRUITING...and 10 more locations
First ischemic stroke
The primary aim is to compare the treatment efficacy of amlodipine-folic acid (5.8 mg/d) vs. amlodipine besylate (5.0 mg/d) for the prevention of first ischemic stroke among the eligible participants with MTHFR 677 CC or CT genotype.
Time frame: By the end of the fifth year from baseline
First ischemic stroke (for refined treatment group comparisons)
We will examine whether there exist significant differences in efficacy in reducing the risk of first ischemic stroke between the following pairs of treatment groups: Among participants with CC genotype Group B vs. Group A Among participants with CT genotype Group B vs. Group A
Time frame: By the end of the fifth year from baseline
First stroke (ischemic and hemorrhagic)
We will examine whether there exist significant differences in efficacy in reducing the risk of first ischemic stroke between the following pairs of treatment groups: Among participants with CC genotype Group B vs. Group A Among participants with CT genotype Group B vs. Group A
Time frame: By the end of the fifth year from baseline
Composite cardiovascular endpoint (first non-fatal stroke, first non-fatal myocardial infarction, cardiovascular death)
We will examine whether there exist significant differences in efficacy in reducing the risk of composite cardiovascular endpoint between the following pairs of treatment groups: Among participants with CC or CT genotype (combined) Group B vs. Group A Among participants with CC genotype Group B vs. Group A Among participants with CT genotype Group B vs. Group A
Time frame: By the end of the fifth year from baseline
Kidney outcomes
The primary kidney outcome is composite kidney outcome, defined as: (1) a decrease in eGFR of 30% or more and to a level of less than 60 mL/min/1.73 m² if the baseline eGFR is 60 mL/min/1.73 m² or more, or (2) a decrease in eGFR of 50% or more if the baseline eGFR is less than 60 mL/min/1.73 m², or (3) end-stage kidney disease (ESKD) (eGFR \<15 mL/min/1.73m² or dialysis or kidney transplantation). Secondary kidney outcomes: (1) eGFR decline ≥40% from baseline, or end-stage kidney disease; (2) annual rate of relative decline in eGFR; (3) incidence of proteinuria or progression of proteinuria. We will examine whether there exist significant differences in efficacy in reducing the risk of kidney outcomes between the following pairs of treatment groups: Among participants with CC or CT genotype (combined) Group B vs. Group A Among participants with CC genotype Group B vs. Group A Among participants with CT genotype Group B vs. Group A
Time frame: By the end of the fifth year from baseline
First hemorrhagic stroke
We will examine whether there exist significant differences in efficacy in reducing the risk of the first hemorrhagic stroke between the following pair of treatment groups: Participants with CC or CT genotype (combined) Group B vs. Group A
Time frame: By the end of the fifth year from baseline
First myocardial infarction
We will examine whether there exist significant differences in efficacy in reducing the risk of the first myocardial infarction between the following pair of treatment groups: Participants with CC or CT genotype (combined) Group B vs. Group A
Time frame: By the end of the fifth year from baseline
First coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI])
We will examine whether there exist significant differences in efficacy in reducing the risk of the first coronary revascularization between the following pair of treatment groups: Participants with CC or CT genotype (combined) Group B vs. Group A
Time frame: By the end of the fifth year from baseline
Cardiovascular death
We will examine whether there exist significant differences in efficacy in reducing the risk of the cardiovascular death between the following pair of treatment groups: Participants with CC or CT genotype (combined) Group B vs. Group A
Time frame: By the end of the fifth year from baseline
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