China Stroke Primary Prevention Trial 2 for Participants with H-type Hypertension and MTHFR 677 CC/CT Genotype (CSPPT2-CC/CT) (CSPPT2-CC/CT)

Comparative Efficacy of Amlodipine Folic Acid Vs. Amlodipine on the Risk of First Ischemic Stroke Among Participants with H-type Hypertension and MTHFR 677 CC/CT Genotype: a Multi-center, Randomized, Double-blind, Double-dummy, Controlled Clinical Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Hypertension; MTHFR 677 CC or CT Genotype; Elevated Plasma Homocysteine (Hcy≥10µmol/L); Insufficient Plasma Folate Levels (<12ng/mL)
• Intervention / Treatment: Drug: Amlodipine besylate; Drug: Amlodipine-folic acid placebos; Drug: Amlodipine besylate and folic acid; Drug: Amlodipine placebos

Detailed Description

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
• Enrollment (Estimated): 32000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Minqing Tian, PhD; Phone Number: 86-18818680849; Email: tianminqing@163.com

Study Locations

• China
  • Anhui
    • Bengbu, Anhui, China, 233004
      • Not yet recruiting
      • First Affiliated Hospital of Bengbu Medical University
      • Contact: Hongju Wang, MD; Phone Number: 13955231336; Email: 1649134019@qq.com
      • Contact: Hongju Wang, MD
    • Bozhou, Anhui, China
      • Not yet recruiting
      • Bozhou
      • Contact: Rongyan Jiang, MD
    • Chizhou, Anhui, China
      • Not yet recruiting
      • Chizhou People's Hospital
      • Contact: Xiaodong Xu, MD
    • Fuyang, Anhui, China
      • Not yet recruiting
      • Taihe County People's Hospital
      • Contact: Shuguang Zhao, MD
      • Contact: Yongjun Zhai, MD
  • Beijing
    • Beijing, Beijing, China
      • Not yet recruiting
      • Peking University First Hospital
      • Contact: Yong Huo, MD
  • Guangdong
    • Yangjiang, Guangdong, China
      • Not yet recruiting
      • Yangjiang People's Hospital
      • Contact: Jiaman Ou, MD
  • Guizhou
    • Guiyang, Guizhou, China
      • Not yet recruiting
      • The Affiliated Hospital of Guizhou Medical University
      • Contact: Wei Li, MD
      • Contact: Fang Wei, MD
  • Hunan
    • Huaihua, Hunan, China
      • Not yet recruiting
      • The First Affiliated Hospital of Hunan University of Medicine
      • Contact: Bifeng Tan
      • Contact: Bifeng Tan, MD
    • Loudi, Hunan, China
      • Not yet recruiting
      • Loudi Central Hospital
      • Contact: Weimin Hu, MD
  • Jiangsu
    • Lianyungang, Jiangsu, China
      • Not yet recruiting
      • The Second People's Hospital of Lianyungang
      • Contact: Liming Sun, MD
    • Lianyungang, Jiangsu, China, 222042
      • Recruiting
      • Lianyungang Oriental Hospital
      • Contact: Huanxian Chang, MD; Phone Number: 15261379733; Email: fsd_000@163.com
      • Contact: Huanxian Chang, MD
    • Lianyungang, Jiangsu, China
      • Not yet recruiting
      • The first people's hospital of Lianyungang
      • Contact: Hui Shi, MD
    • Yancheng, Jiangsu, China
      • Not yet recruiting
      • Yancheng First People's Hospital
      • Contact: Qilong Zuo, MD
      • Contact: Qilong Zuo
  • Jiangxi
    • Ganzhou, Jiangxi, China
      • Not yet recruiting
      • The First Affiliated Hospital of Gannan Medical University,
      • Contact: Xiaofeng Zou, MD
      • Contact: Yiming Zhong, MD
    • Nanchang, Jiangxi, China
      • Not yet recruiting
      • Second Affiliated Hospital of Nanchang University
      • Contact: Xiaoshu Cheng, MD
  • Shaanxi
    • Weinan, Shaanxi, China
      • Not yet recruiting
      • Weinan Central Hospital
      • Contact: Junnong Li, MD
  • Shandong
    • Zaozhuang, Shandong, China, 277599
      • Not yet recruiting
      • Tengzhou Central People's Hospital
      • Contact: Yong Li, MD; Phone Number: 13563295777; Email: tzlysd123@163.com
      • Contact: Yong Li, MD
  • Sichuan
    • Chengdu, Sichuan, China
      • Not yet recruiting
      • Chengdu Fifth People's Hospital
      • Contact: Lihua Zhou, MD
    • Deyang, Sichuan, China
      • Not yet recruiting
      • Deyang People's Hospital
      • Contact: Xiaojian Deng, MD
    • Luzhou, Sichuan, China
      • Not yet recruiting
      • The Affiliated Hospital of Southwest Medical University
      • Contact: Juyi Wan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men and women, aged ≥45 and <75 years;
2. Hypertension: Previously diagnosed with primary hypertension and has been taking antihypertensive medication within the past two weeks; OR has not been taking antihypertensive medications within the last two weeks, but meets the following criteria for hypertension: SBP≥140 mmHg and/or DBP≥90 mmHg (average of at least 2 measurements each time) at two separate (not on the same day) clinical visits;
3. MTHFR 677 CC or CT genotype (based on the test results from the central laboratory during the screening period or a previous official test report from a laboratory with medical testing qualifications);
4. Plasma total homocysteine ≥10 µmol/L;
5. Serum folate level <12 ng/mL;
6. Has voluntarily agreed to participate and provided signed informed consent.

Randomized-treatment phase inclusion criteria:

1. Good compliance during the run-in period, and unlikely to discontinue treatment;
2. No stroke or cardiovascular events during the run-in period;
3. The participant voluntarily agrees to continue the study.

Exclusion Criteria:

1. Previously diagnosed secondary hypertension;
2. Previously diagnosed stroke;
3. Previously diagnosed myocardial infarction;
4. Previously diagnosed heart failure;
5. Previously diagnosed atrial fibrillation;
6. Cardio-cerebral-kidney revascularization and/or other large arterial stent;
7. Currently on dialysis, or diagnosed with stage 4-5 chronic kidney disease, or eGFR <30 mL/ min/1.73m²;
8. Known to have congenital (such as aortic stenosis) or acquired organic heart disease;

9. Known to have any of the following severe diseases or conditions:

   1. 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 test 3 times higher than normal, or ALB≤30g/L); iii. Subtotal gastrectomy and/or gastrojejunostomy;
   2. Respiratory system: previously diagnosed with pulmonary heart disease;
   3. Presence of malignant tumors or other severe diseases;
   4. Presence of long-term gastrointestinal symptoms such as anorexia, decreased appetite, nausea, and abdominal bloating;
   5. Previously diagnosed with vitamin B12 deficiency and/or its related diseases.
10. 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 conditions;
11. Prior history of significant intolerance due to adverse reactions resulting from usage of amlodipine or other CCBs, valsartan or other ARBs, indapamide or other similar diuretics, metoprolol tartaric acid or other beta-blockers, or any drugs or health products containing folate or folic acid;
12. Regular consumption of folic acid or vitamin B compounds, or other compounds containing folic acid in the past 3 months;

13. The presence of any of the following conditions that could negatively influence a participant's ability to consent or participate in the trial:

    1. Dementia;
    2. Severe mental disorders;
    3. Inability to express informed consent;
    4. 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;
    5. History of poor compliance when taking antihypertensive medications or is expected to have poor compliance during the study;
14. Refusal to participate, or inability to modify current drug regimen;
15. Women who are pregnant or breastfeeding; or subjects of childbearing potential who are unwilling or unable to use effective contraception during the study period.
16. Within one month prior to the first visit, having participated in any clinical trial for a drug that has not yet been officially approved by the state or 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.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CC with amlodipine 5mg/d; For subjects with the MTHFR CC genotype, amlodipine (5mg) + amlodipine-folic acid (dummy), once daily, taken orally in the morning after waking-up.	Drug: Amlodipine besylate; 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).; Other Names: Amlodipine; Drug: Amlodipine-folic acid placebos; An Amlodipine folic acid placebo is a dummy pill of an amlodipine folic acid tablet with an identical appearance.; Other Names: Amlodipine-folic acid (dummy)
Experimental: CC with amlodipine folic acid 5.8mg/d; For subjects with the MTHFR CC genotype, amlodipine-folic acid (5.8mg) + amlodipine (dummy), once daily, taken orally in the morning after waking-up.	Drug: Amlodipine besylate and folic acid; 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).; Other Names: Anye; Amlodipine folic acid; Drug: Amlodipine placebos; An amlodipine placebo is a dummy pill of an amlodipine tablet with an identical appearance.; Other Names: Amlodipine (dummy)
Active Comparator: CT with amlodipine 5mg/d; For subjects with the MTHFR CT genotype, amlodipine (5mg) + amlodipine-folic acid (dummy), once daily, taken orally in the morning after waking-up.	Drug: Amlodipine besylate; 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).; Other Names: Amlodipine; Drug: Amlodipine-folic acid placebos; An Amlodipine folic acid placebo is a dummy pill of an amlodipine folic acid tablet with an identical appearance.; Other Names: Amlodipine-folic acid (dummy)
Experimental: CT with amlodipine folic acid 5.8mg/d; For subjects with the MTHFR CT genotype, amlodipine-folic acid (5.8mg) + amlodipine (dummy), once daily, taken orally in the morning after waking-up.	Drug: Amlodipine besylate and folic acid; 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).; Other Names: Anye; Amlodipine folic acid; Drug: Amlodipine placebos; An amlodipine placebo is a dummy pill of an amlodipine tablet with an identical appearance.; Other Names: Amlodipine (dummy)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	By the end of the fifth year from baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	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	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	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	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	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	By the end of the fifth year from baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malignant tumors	We will examine whether there exist significant differences in efficacy in reducing the risk of malignant tumors between the following pair of treatment groups: Participants with CC or CT genotype (combined) Group B vs. Group A	By the end of the fifth year from baseline
All-cause mortality	We will examine whether there exist significant differences in efficacy in reducing the risk of all-cause mortality between the following pair of treatment groups: Participants with CC or CT genotype (combined) Group B vs. Group A	By the end of the fifth year from baseline
Blood pressure levels	We will examine whether there exist significant differences in treatment efficacy on the blood pressure levels 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	1) Blood pressure levels at one year, three-year and at the end of follow-up(up to 5 years). 2) Average blood pressure levels across all visits in the first and third years of follow-up, as well as for the entire follow-up period (up to 5 years).
Blood pressure variability	We will examine whether there exist significant differences in treatment efficacy on the blood pressure variability 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	Average blood pressure variability across all visits in the first and third years of follow-up, and across all visits throughout the entire follow-up period (up to 5 years).
Blood pressure target achievement rates	We will examine whether there exist significant differences in treatment efficacy on the blood pressure target achievement rates 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	1) Blood pressure target achievementrates at 1-year, 3-year and at the end of follow-up(up to 5 years). 2) Average bloodpressure target achievement rates across all visits in the first and third years of follow-up, and for the entire follow-up period.]
Serum folate level	We will examine whether there exist significant differences in treatment efficacy on the serum folate levels 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	Serum folate levels at one year, three-year and at the end of follow-up(up to 5 years).
Serum folate change	We will examine whether there exist significant differences in treatment efficacy on the serum folate changes 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	Serum folate changes at one year, three-year and at the end of follow-up(up to 5 years).
Plasma tHcy level	We will examine whether there exist significant differences in treatment efficacy on the plasma total homocysteine levels 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	Plasma total homocysteine levels at one year, three-year and at the end of follow-up(up to 5 years).
Plasma tHcy change	We will examine whether there exist significant differences in treatment efficacy on the plasma total homocysteine changes 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	Plasma total homocysteine changes at one year, three-year and at the end of follow-up(up to 5 years).

Collaborators and Investigators

• Sponsor: Shenzhen Ausa Pharmed Co.,Ltd
• Collaborators: Peking University First Hospital; The Affiliated Hospital Of Guizhou Medical University; Second Affiliated Hospital of Nanchang University; Chengdu Fifth People's Hospital; The First People's Hospital of Lianyungang; Tengzhou Central People's Hospital; The Affiliated Hospital Of Southwest Medical University; Weinan Central Hospital; Yancheng First People's Hospital; Bozhou people's hospital; Chizhou people's hospital; Loudi Central Hospital; The First Affiliated Hospital of Gannan Medical University; Lianyungang Oriental Hospital; The First Affiliated Hospital of HuNan University of Medicine; Deyang People's Hospital; Yangjiang People's Hospital; The First Affiliated Hospital of Bengbu Medical University; Shenzhen Prospective Medical Technology Co., LTD; TAIHE country people's hospital; Lianyungang Second People's Hospital
• Investigators: Principal Investigator: Yong Huo, MD, PhD, Peking University First Hospital

Publications and helpful links

General Publications

• Kjeldsen SE, Julius S, Hedner T, Hansson L. Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials. Blood Press. 2001;10(4):190-2. doi: 10.1080/08037050152669684. No abstract available.
• Collaboration HLT. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8.
• Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005 Oct;82(4):806-12. doi: 10.1093/ajcn/82.4.806.
• Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M, Stoll C, Alembik Y, Dott B, Czeizel AE, Gelman-Kohan Z, Scarano G, Bianca S, Ettore G, Tenconi R, Bellato S, Scala I, Mutchinick OM, Lopez MA, de Walle H, Hofstra R, Joutchenko L, Kavteladze L, Bermejo E, Martinez-Frias ML, Gallagher M, Erickson JD, Vollset SE, Mastroiacovo P, Andria G, Botto LD. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003 Aug;40(8):619-25. doi: 10.1136/jmg.40.8.619. No abstract available. Erratum In: J Med Genet. 2004 May;41(5):400. Redlund, M [corrected to Renlund, M].
• Xu X, Li J, Sheng W, Liu L. Meta-analysis of genetic studies from journals published in China of ischemic stroke in the Han Chinese population. Cerebrovasc Dis. 2008;26(1):48-62. doi: 10.1159/000135653. Epub 2008 May 30.
• Dong Q, Tang G, He M, Cai Y, Cai Y, Xing H, Sun L, Li J, Zhang Y, Fan F, Wang B, Sun N, Liu L, Xu X, Hou F, Shen H, Xu X, Huo Y. Methylenetetrahydrofolate reductase C677T polymorphism is associated with estimated glomerular filtration rate in hypertensive Chinese males. BMC Med Genet. 2012 Aug 16;13:74. doi: 10.1186/1471-2350-13-74.
• Huang X, Li Y, Li P, Li J, Bao H, Zhang Y, Wang B, Sun N, Wang J, He M, Yin D, Tang G, Chen Y, Cui Y, Huang Y, Hou FF, Qin X, Huo Y, Cheng X. Association between percent decline in serum total homocysteine and risk of first stroke. Neurology. 2017 Nov 14;89(20):2101-2107. doi: 10.1212/WNL.0000000000004648. Epub 2017 Oct 13.
• Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, Tang G, Wang B, Chen D, He M, Fu J, Cai Y, Shi X, Zhang Y, Cui Y, Sun N, Li X, Cheng X, Wang J, Yang X, Yang T, Xiao C, Zhao G, Dong Q, Zhu D, Wang X, Ge J, Zhao L, Hu D, Liu L, Hou FF; CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015 Apr 7;313(13):1325-35. doi: 10.1001/jama.2015.2274.
• Qin X, Li J, Cui Y, Liu Z, Zhao Z, Ge J, Guan D, Hu J, Wang Y, Zhang F, Xu X, Wang X, Xu X, Huo Y. MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults. Nutr J. 2012 Jan 10;11:2. doi: 10.1186/1475-2891-11-2.
• Qin X, Li J, Cui Y, Liu Z, Zhao Z, Ge J, Guan D, Hu J, Wang Y, Zhang F, Xu X, Wang X, Xu X, Huo Y. Effect of folic acid intervention on the change of serum folate level in hypertensive Chinese adults: do methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms affect therapeutic responses? Pharmacogenet Genomics. 2012 Jun;22(6):421-8. doi: 10.1097/FPC.0b013e32834ac5e8.
• Qin X, Li J, Zhang Y, Ma W, Fan F, Wang B, Xing H, Tang G, Wang X, Xu X, Xu X, Huo Y. Prevalence and associated factors of diabetes and impaired fasting glucose in Chinese hypertensive adults aged 45 to 75 years. PLoS One. 2012;7(8):e42538. doi: 10.1371/journal.pone.0042538. Epub 2012 Aug 3.
• Qin X, Li Y, Sun N, Wang H, Zhang Y, Wang J, Li J, Xu X, Liang M, Nie J, Wang B, Cheng X, Li N, Sun Y, Zhao L, Wang X, Hou FF, Huo Y. Elevated Homocysteine Concentrations Decrease the Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitors in Hypertensive Patients. Arterioscler Thromb Vasc Biol. 2017 Jan;37(1):166-172. doi: 10.1161/ATVBAHA.116.308515. Epub 2016 Nov 10.

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2024
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): June 30, 2030

Study Registration Dates

• First Submitted: July 13, 2021
• First Submitted That Met QC Criteria: July 13, 2021
• First Posted (Actual): July 23, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 24, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Folic acid; Ischemic stroke; Homocysteine; MTHFR C677T genotype
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypertension; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Micronutrients; Vitamins; Calcium Channel Blockers; Vasodilator Agents; Hematinics; Antihypertensive Agents; Folic Acid; Amlodipine; Vitamin B Complex
• Other Study ID Numbers: CSPPT2-CC/CT_2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No