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

NCT04974151 | Recruiting Phase 4 DMC

• 1 other identifier: CSPPT2-TT_2020
• Study Type: interventional
• Target: 24,000
• Locations: 1 country
• Sites: 20

Brief Summary

This is a multi-center, randomized, double-blind, triple-dummy, controlled trial in 24,000 Chinese men and women with hypertension and MTHFR 677 TT genotype. The study participants will be randomized to one of the three treatment groups: 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. Group C: amlodipine folic acid 5.8mg tablet plus 5-methyltetrahydrofolate (5-MTHF, 0.4mg), taken orally, once daily. The primary endpoint is first ischemic stroke.

Conditions

Hypertension; MTHFR 677 TT Genotype

Keywords

Folic acid; Homocysteine; MTHFR 677 TT genotype; Randomized controlled trial; Ischemic stroke; 5-MTHF

Outcome Measures

Primary Outcomes (1)

• First ischemic stroke

  The primary aim of the trial is to determine whether amlodipine folic acid tablets (including Group B and Group C), compared to amlodipine alone (Group A), can further reduce the risk of first ischemic stroke among eligible participants with hypertension and the MTHFR 677 TT genotype.

  By the end of the fifth year of the study

Secondary Outcomes (8)

• First ischemic stroke (for refined treatment group comparisons)

  By the end of the fifth year of the study

• First stroke (ischemic and hemorrhagic)

  By the end of the fifth year from baseline

• Composite cardiovascular endpoint (first non-fatal stroke, first non-fatal myocardial infarction, cardiovascular death)

  By the end of the fifth year from baseline

• Kidney outcomes

  By the end of the fifth year from baseline

• First hemorrhagic stroke

  By the end of the fifth year from baseline

Other Outcomes (9)

• Malignant tumors

  By the end of the fifth year of the study

• All-cause mortality

  By the end of the fifth year of the study

• Blood pressure levels

  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).

Study Arms (3)

Amlodipine (5mg/d)

ACTIVE COMPARATOR

Amlodipine 5mg x1 tablet + Amlodipine folic acid (dummy) x1 tablet + 5-MTHF (dummy) x2 tablets, taken orally, in the morning after waking up. Amlodipine tablets, amlodipine folic acid placebos, and 5-MTHF placebos are provided in aluminum-plastic blister plate. 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 50 plates, each plate includes a total of 8 tablets arranged as follows: amlodipine 5mg x2 tablets + amlodipine folic acid (dummy) x2 tablets + 5-MTHF (dummy) x4 tablets. Affixed to the package is the randomized treatment drug label (400 tablets/package, 4 tablets/day).

Drug: Amlodipine besylate; Drug: Amlodipine folic acid placebo; Drug: 5-MTHF Placebos

Amlodipine folic acid (5.8mg/d)

EXPERIMENTAL

Amlodipine folic acid 5.8mg x1 tablet + amlodipine (dummy) x1 tablet + 5-MTHF (dummy) x2 tablets, taken orally, in the morning after waking up. Amlodipine folic acid tablets, amlodipine placebos, and 5-MTHF placebos are provided in aluminum-plastic blister plate. 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 50 plates, each plate includes a total of 8 tablets arranged as follows: amlodipine folic acid 5.8mg x2 tablets + amlodipine (dummy) x2 tablets + 5-MTHF (dummy) x4 tablets. Affixed to the package is the randomized treatment drug label (400 tablets/package, 4 tablets/day).

Drug: Amlodipine besylate And Folic Acid; Drug: Amlodipine placebo; Drug: 5-MTHF Placebos

Amlodipine folic acid (5.8mg/d) + 5-MTHF (0.4mg/d)

EXPERIMENTAL

Amlodipine folic acid 5.8mg x1 tablet + 5-methyltetrahydrofolate 0.2mg x2 tablets + amlodipine (dummy) x1 tablet, taken orally, in the morning after waking up. Amlodipine folic acid tablets, 5-MTHF, and amlodipine placebos are provided in aluminum-plastic blister plate. 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 50 plates, each plate includes a total of 8 tablets arranged as follows: amlodipine folic acid 5.8mg x2 tablets + amlodipine (dummy) x2 tablets + 5-MTHF, 0.2mg x4 tablets. Affixed to the package is the randomized treatment drug label (400 tablets/package, 4 tablets/day).

Drug: Amlodipine besylate And Folic Acid; Drug: 5-methyltetrahydrofolate (5-MTHF); Drug: Amlodipine placebo

Interventions

Amlodipine besylate DRUG

The amlodipine used in this study is a listed product.

Also known as: Amlodipine

Amlodipine (5mg/d)

Amlodipine besylate And Folic Acid DRUG

The amlodipine besylate and folic acid tablets have been approved for listing by the China Food and Drug Administration, approval number: Zhunzi H20180020.

Also known as: Amlodipine Folic Acid, Anye

Amlodipine folic acid (5.8mg/d); Amlodipine folic acid (5.8mg/d) + 5-MTHF (0.4mg/d)

5-methyltetrahydrofolate (5-MTHF) DRUG

The 5-MTHF used in this study is a listed product.

Also known as: 5-MTHF

Amlodipine folic acid (5.8mg/d) + 5-MTHF (0.4mg/d)

Amlodipine placebo DRUG

Amlodipine placebos are dummy pills of amlodipine with identical appearance.

Also known as: Amlodipine (dummy)

Amlodipine folic acid (5.8mg/d); Amlodipine folic acid (5.8mg/d) + 5-MTHF (0.4mg/d)

Amlodipine folic acid placebo DRUG

Amlodipine folic acid placebos are dummy pills of amlodipine folic acid with identical appearance.

Also known as: Amlodipine folic acid (dummy)

Amlodipine (5mg/d)

5-MTHF Placebos DRUG

5-MTHF placebos are the dummy pills of 5-MTHF with identical appearance.

Also known as: 5-MTHF (dummy)

Amlodipine (5mg/d); Amlodipine folic acid (5.8mg/d)

Eligibility Criteria

• Age: 45 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women, aged ≥45 and \<75 years.
• 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.
• MTHFR 677 TT 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).
• Voluntarily participates and has given signed informed consent.
• Good compliance during the run-in period, and unlikely to discontinue treatment;
• No stroke or cardiovascular events during the run-in period;
• The participant voluntarily agrees to continue the study.

You may not qualify if:

• Previously diagnosed secondary hypertension;
• Previously diagnosed stroke;
• Previously diagnosed myocardial infarction;
• Previously diagnosed heart failure;
• Previously diagnosed atrial fibrillation;
• Cardio-cerebral-kidney revascularization and/or other large arterial stent;
• Currently on dialysis, or diagnosed with stage 4-5 chronic kidney disease, or 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:
• 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;
• Respiratory system: previously diagnosed with pulmonary heart disease;
• Presence of malignant tumors or other severe diseases;
• Presence of long-term gastrointestinal symptoms such as ; anorexia, decreased appetite, nausea, and abdominal bloating;
• Previously diagnosed with vitamin B12 deficiency and/or its related 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 conditions;

Sponsors & Collaborators

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

Study Sites (20)

First Affillated Hospital of Bengbu Medical University

Bengbu, Anhui, 233004, China

NOT YET RECRUITING

Bozhou People's Hospital

Bozhou, Anhui, China

NOT YET RECRUITING

Chizhou People's Hospital

Chizhou, Anhui, China

NOT YET RECRUITING

Taihe County People's Hospital

Fuyang, Anhui, China

NOT YET RECRUITING

Peking University First Hospital

Beijing, Beijing Municipality, China

NOT YET RECRUITING

Yangjiang People's Hospital

Yangjiang, Guangdong, China

NOT YET RECRUITING

The Affiliated Hospital of Guizhou Medical University

Guiyang, Guizhou, China

NOT YET RECRUITING

The First Affiliated Hospital of Hunan University of Medicine

Huaihua, Hunan, China

NOT YET RECRUITING

Loudi Central Hospital

Loudi, Hunan, China

NOT YET RECRUITING

Lianyungang Oriental Hospital

Lianyungang, Jiangsu, 222042, China

RECRUITING

The First People's Hospital of Lianyungang

Lianyungang, Jiangsu, China

NOT YET RECRUITING

The Second People's Hospital of Lianyungang

Lianyungang, Jiangsu, China

NOT YET RECRUITING

Yancheng First People's Hospital

Yancheng, Jiangsu, China

NOT YET RECRUITING

The First Affiliated Hospital of Gannan Medical University

Ganzhou, Jiangxi, China

NOT YET RECRUITING

Second Affiliated Hospital of Nanchang University

Nanchang, Jiangxi, China

NOT YET RECRUITING

Weinan Central Hospital

Weinan, Shaanxi, China

NOT YET RECRUITING

Tengzhou Central People's Hospital

Zaozhuang, Shandong, 277599, China

NOT YET RECRUITING

Chengdu Fifth People's Hospital

Chengdu, Sichuan, China

NOT YET RECRUITING

Deyang People's Hospital

Deyang, Sichuan, China

NOT YET RECRUITING

The Affiliated Hospital of Southwest Medical University

Luzhou, Sichuan, China

NOT YET RECRUITING

Related Publications (12)

• 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.

  PMID: 11800055 BACKGROUND

• 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.

  PMID: 9569395 BACKGROUND

• 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.

  PMID: 16210710 BACKGROUND

• 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.

  PMID: 12920077 BACKGROUND

• 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.

  PMID: 22230384 BACKGROUND

• 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.

  PMID: 21869730 BACKGROUND

• 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.

  PMID: 18511872 BACKGROUND

• 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.

  PMID: 22880024 BACKGROUND

• 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.

  PMID: 22897803 BACKGROUND

• 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.

  PMID: 25771069 BACKGROUND

• 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.

  PMID: 29030456 BACKGROUND

• 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.

  PMID: 27834686 BACKGROUND

MeSH Terms

Conditions

Hypertension; Ischemic Stroke

Interventions

Amlodipine; Folic Acid; 5-methyltetrahydrofolate

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jianping Li, MD, PhD

  Peking University First Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Minqing Tian, PhD

CONTACT

86-18818680849; tianminqing@163.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Multicenter, randomized, controlled, double-blind, triple-dummy clinical trial

Study Record Dates

• First Submitted: July 13, 2021
• First Posted: July 23, 2021
• Study Start: August 22, 2024
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): June 30, 2029
• Last Updated: February 26, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (20)