China Stroke Primary Prevention Trial for Subjects With Hypertension and MTHFR 677 TT Genotype (CSPPT2-TT)

Study Overview
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Brief Summary
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This is a multicenter, randomized, controlled clinical trial. It aims to investigate the treatment effects of amlodipine folic acid, and its combination of 5-methyltetrahydrofolate (5-MTHF), compared to amlodipine, on reducing the risk of first ischemic stroke among those participants with the MTHFR 677 TT genotype and hypertension. This study consists of 3 phases: Screening, Run-in period (0 or 2 weeks), and randomized treatment (5 years), with a prospective, randomized, open-label, blinded end-point design.

Detailed Description
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This study consists of 3 phases: Screening, Run-in period, Randomized treatment. Phase I: Screening (V0) The purpose of phase I is to obtain informed consent and make a preliminary assessment of the patient. At the first screening visit (V0), or prior to the official treatment visit, a clinical examination will be performed to determine the patient's clinical diagnosis and to determine eligibility for inclusion in the study. General demographic information will be obtained and questions related to the inclusion/exclusion criteria of this study will be asked. Additionally, this will be the time to discuss the impact of participant vacation/travel plans on adherence and compliance with the trial protocol. Phase II: Run-in Period (VD) Eligible patients who have not used antihypertensive drugs of Dihydropyridine Calcium Channel Blockers (CCBs) in the past two months, or who require further observation such as patients taking dihydropyridine CCBs but under the circumstances that may affect the evaluation of compliance and safety to patients like taking medicine irregularly, self-medication, and poor blood pressure control, will begin the treatment of amlodipine (5mg/d) for a 2-week run-in period. Those patients who have been taking antihypertensive drugs of dihydropyridine CCBs in the past two months and who report no adverse reactions, will skip the run-in period and directly begin the randomized treatment phase. The primary purpose of this phase is to assess participant compliance for following the amlodipine treatment regimen as well as to observe the participant's tolerance to amlodipine, so as to avoid admitting those participants with poor compliance or an intolerance to amlodipine, into the randomized treatment phase. Phase III: Randomized Treatment (V1-V21) The third phase consists of a 5-year period of randomized treatment. Patients who remain eligible for participation in the study will be randomized into 3 treatment groups: either amlodipine only tablets (5mg/d), or amlodipine folic acid tablets (5.8mg/d), or amlodipine folic acid tablets (5.8mg/d) + 5-MTHF (0.4mg/d). During the 5-year randomized treatment period, other antihypertensive drugs can be combined with the treatment drug to achieve blood pressure control, including Candesartan (8mg/d) or/and Indapamide (1.5mg/d). Patients will be followed-up every 3 months during the treatment period, and the treatment drug will be distributed at each visit. During this period, participants should continue to avoid taking medications that may interfere with the evaluation of treatment efficacy. After the Run-in Period, eligible participants, stratified by research centers, were randomly assigned, in a 1:1 ratio, to receive the two study treatments. Randomization was performed centrally by means of a computer-generated random-number sequence. This study plans to enroll 24,000 participants. Based on the results of previous studies, the annual incidence of first ischemic stroke in people with hypertension and the MTHFR TT genotype without folic acid supplementation is 0.64%. Assuming that the 5-year incidence of first ischemic stroke in the amlodipine group is greater than 2.5%, this study could observe a relative risk difference of more than 25% between the groups with over 80% power at a two-sided significance level of α=0.05. For an assumed annual incidence of first ischemic stroke greater than 3.5%, a relative risk difference of over 20% between the groups could be observed with 80% or more power. For every 200 confirmed primary outcome events, an interim analysis will be conducted. This study anticipates conducting 4 interim analyses. 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 will be α=0.05.

Official Title
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Comparative Efficacy of Amlodipine Folic Acid vs. Amlodipine on the Risk of First Ischemic Stroke Among Patients With Hypertension and MTHFR 677 TT Genotype: A Multi-center, Randomized, Controlled Clinical Trial

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Amlodipine besylate tablets
* Drug: Amlodipine besylate And Folic Acid Tablets
* Drug: 5-methyltetrahydrofolate (5-MTHF)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, aged 50-75 years Previously diagnosed with primary hypertension and has been taking antihypertensive medication within the past two weeks, OR has not been taking antihypertensive medication within the last two weeks but meets the following criteria for hypertension: on two separate (not on the same day) visits in a clinical setting, blood pressure measurements (average of 3 measurements each time) showed SBP≥140 mmHg and/or DBP≥90 mmHg; MTHFR 677 TT genotype (based on test results from the central laboratory in the screening period or a previous official test report from the laboratory with medical testing qualifications); Voluntarily participates and has given signed, informed consent. Randomized-treatment phase inclusion criteria: Good compliance during the run-in phase (assessed by a medical compliance survey for predicting patient compliance); Tolerance of amlodipine besylate 5.0mg tablets (does not result in discontinuation of medication due to adverse effects); No cardiovascular or cerebrovascular events occurred during the run-in phase; Voluntarily agrees to continue with participation in the study. Exclusion Criteria: Previously diagnosed secondary hypertension; Previously diagnosed stroke; Previously diagnosed myocardial infarction; Previously diagnosed heart failure; Cardio-cerebral-kidney revascularization and/or other large arterial stenting; Currently on dialysis, OR diagnosed with stage 4-5 chronic kidney disease, OR estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m²; Known to have congenital (such as aortic stenosis) or acquired organic heart disease; Known to have any of the following severe diseases or conditions: a. Digestive system i. Previously diagnosed with any form of viral hepatitis that is currently still in the active phase; ii. Abnormal liver function test before enrollment (any of ALT, AST, GGT, TBIL, DBIL testing 3 times higher than normal, ALB ≤ 30g/L); iii. Subtotal gastrectomy and/or gastrojejunostomy; b. Respiratory system i. Previously diagnosed with pulmonary heart disease and/or chronic obstructive pulmonary disease; c. Presence of malignant tumors or other severe diseases; Participant, at the investigator's discretion, is assessed to be unsuitable for the study, for reasons including but not limited to the presence of abnormal laboratory results, or clinical abnormalities/signs; Prior history of significant intolerance due to adverse reactions resulting from usage of amlodipine or other CCBs, candesartan or other ARBs, hydrochlorothiazide or other similar diuretics, or any drugs or health products containing folate or folic acid; Regular consumption of folic acid or compounds containing folic acid in the past 3 months; Presence of any of the following conditions that could negatively influence a participant's ability to consent or participate in the trial: Dementia; Severe mental disorders; Inability to express informed consent; Unlikely to complete the study follow-up as specified by the protocol, or plans to relocate outside of the study area in the near future; History of poor compliance when taking antihypertensive medications or is expected to have poor compliance during the study; Refusal to participate, or inability to modify current drug regimen; Within one month of the first visit, participating in any clinical trial for any drug that has yet to be officially approved by the state and is not currently approved for sale, OR currently participating in any clinical trial that could potentially impact the results of this study (medication use, drug efficacy, drug interaction, etc.)

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, randomized, controlled clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: amlodipine (5mg/d)<br>Amlodipine besylate tablets (5mg/d) | Drug: Amlodipine besylate tablets<br>* The amlodipine used in this study is a listed product. All drugs used in the Randomized Treatment Period of this study will be packed into bottles with the same outer appearance and corresponding labels of the clinical trial (100 tablets/bottle).<br>* Other names: Amlodipine;|
| Experimental: amlodipine folic acid (5.8mg/d)<br>Amlodipine besylate and folic acid tablets (5mg:0.8mg) | Drug: Amlodipine besylate And Folic Acid Tablets<br>* The amlodipine besylate and folic acid tablets have been approved for listing by the China Food and Drug Administration, approval number: Zhunzi H20180020. All drugs used in the Randomized Treatment Period of this study will be packed into bottles with the same outer appearance and corresponding labels of the clinical trial (100 tablets/bottle).<br>* Other names: Anye;|
| Experimental: amlodipine folic acid (5.8mg/d) + 5-MTHF (0.4mg/d)<br>Amlodipine besylate and folic acid tablets (5mg:0.8mg) with 0.4mg/d 5-MTHF | Drug: Amlodipine besylate And Folic Acid Tablets<br>* The amlodipine besylate and folic acid tablets have been approved for listing by the China Food and Drug Administration, approval number: Zhunzi H20180020. All drugs used in the Randomized Treatment Period of this study will be packed into bottles with the same outer appearance and corresponding labels of the clinical trial (100 tablets/bottle).<br>* Other names: Anye;Drug: 5-methyltetrahydrofolate (5-MTHF)<br>* The 5-MTHF used in this study is a listed product. All drugs used in the Randomized Treatment Period of this study will be packed into bottles with the same outer appearance and corresponding labels of the clinical trial (0.2mg/tablet, 200 tablets/bottle).<br>* Other names: 5-MTHF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First ischemic stroke | This study investigates whether, among patients with hypertension and the MTHFR 677 TT genotype, there is a statistically significant difference in treatment efficacy among the amlodipine folic acid (5.8 mg/d) group, the amlodipine folic acid with 0.4mg/d 5-MTHF group, and the amlodipine besylate (5.0 mg/d) group, for the prevention of first ischemic stroke. The risk (hazard ratio) and time of the event of first ischemic stroke will be measured by Kaplan-Meier survival analyses, log-rank tests, and Cox proportional-hazards regression models at the significance level of α=0.05 (two-sided test). | By the end of the fifth year from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular related events | This study investigates the treatment effects of amlodipine folic acid (5.8 mg/d) and its combination with 0.4mg 5-MTHF, compared to amlodipine besylate (5.0 mg/d), on the following six endpoints: combined cardiovascular endpoints (first stroke, first hospitalization from myocardial infarction, first hospitalization from heart failure, or cardiovascular death), first stroke (ischemic or hemorrhagic stroke), first hospitalization due to myocardial infarction, first hospitalization due to heart failure, cardiovascular death, and all-cause death. The risk and time of event of any secondary endpoints will be measured by Kaplan-Meier survival analyses, log-rank tests, and Cox proportional-hazards regression models at the significance level of α=0.05 (two-sided test). | By the end of the fifth year from baseline | 
| Effect of different levels of dosage of folic acid on cardiovascular events | This study investigates the treatment efficacy of amlodipine folic acid with 0.4mg 5-MTHF on secondary endpoints, compared to amlodipine folic acid. The risk and time of event of any secondary endpoints will be measured by Kaplan-Meier survival analyses, log-rank tests, and Cox proportional-hazards regression models at the significance level of α=0.05 (two-sided test). | By the end of the fifth year from baseline | 
| Amlodipine-based multi-antihypertensive drug combinations on cardiovascular events | This study investigates whether, among patients with hypertension and the MTHFR TT genotype who require a multi-drug antihypertensive regimen, there is a statistically significant difference among the combinations of two multi-antihypertensive drugs on each of the following 7 endpoints: first stroke, first ischemic stroke, first hemorrhagic stroke, first hospitalization due to myocardial infarction, first hospitalization due to heart failure, cardiovascular death, and all-cause death. Stratified by different amlodipine-based multi-antihypertensive drug combinations, the risk and time of event of any secondary endpoints in each group will be measured by Kaplan-Meier survival analyses, log-rank tests, and Cox proportional-hazards regression models at the significance level of α=0.05 (two-sided test). | By the end of the fifth year from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Folic acid, Homocysteine, MTHFR C677T, RCT, Ischemic stroke, 5-MTHF