Clinical trial NCT04974151: China Stroke Primary Prevention Trial 2 for Participants With Hypertension and MTHFR 677 TT Genotype
Official title: Comparative Efficacy of Amlodipine Folic Acid vs. Amlodipine on the Risk of First Ischemic Stroke Among Participants With Hypertension and MTHFR 677 TT Genotype: A Multi-center, Randomized, Double-blind, Triple-dummy, Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hypertension
MTHFR 677 TT Genotype
Keywords: Folic acid
Homocysteine
MTHFR 677 TT genotype
Randomized controlled trial
Ischemic stroke
5-MTHF
Lead sponsor: Shenzhen Ausa Pharmed Co.,Ltd
Sponsor class: INDUSTRY
Collaborators: name: Peking University First Hospital
name: Second Affiliated Hospital of Nanchang University
name: The First People's Hospital of Lianyungang
name: The Affiliated Hospital Of Guizhou Medical University
name: Lianyungang Oriental Hospital
name: Tengzhou Central People's Hospital
name: The First Affiliated Hospital of Bengbu Medical University
name: Shenzhen Prospective Medical Technology Co., LTD
name: Weinan Central Hospital
name: The First Affiliated Hospital of HuNan University of Medicine
name: Loudi Central Hospital
name: Yancheng First People's Hospital
name: TAIHE country people's hospital
name: First Affiliated Hospital of Gannan Medical University
name: Yangjiang People's Hospital
name: Deyang People's Hospital
name: Bozhou people's hospital
name: Chizhou people's hospital
name: Lianyungang Second People's Hospital
name: The Affiliated Hospital Of Southwest Medical University
name: Chengdu Fifth People's Hospital
First posted: 2021-07-23
Enrollment: 24000
Sex: ALL
Minimum age (years): 45
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, randomized, controlled, double-blind, triple-dummy clinical trial
Primary purpose: TREATMENT

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.

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 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.

Eligibility criteria: 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 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).
4. Voluntarily participates and has given 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.).

Primary outcomes:
measure: First ischemic stroke
timeFrame: By the end of the fifth year of the study
Secondary outcomes:
measure: First ischemic stroke (for refined treatment group comparisons)
timeFrame: By the end of the fifth year of the study
measure: First stroke (ischemic and hemorrhagic)
timeFrame: By the end of the fifth year from baseline
measure: Composite cardiovascular endpoint (first non-fatal stroke, first non-fatal myocardial infarction, cardiovascular death)
timeFrame: By the end of the fifth year from baseline
measure: Kidney outcomes
timeFrame: By the end of the fifth year from baseline
measure: First hemorrhagic stroke
timeFrame: By the end of the fifth year from baseline
measure: First myocardial infarction
timeFrame: By the end of the fifth year from baseline
measure: First coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI])
timeFrame: By the end of the fifth year from baseline
measure: Cardiovascular death
timeFrame: By the end of the fifth year from baseline
Other outcomes:
measure: Malignant tumors
timeFrame: By the end of the fifth year of the study
measure: All-cause mortality
timeFrame: By the end of the fifth year of the study
measure: Blood pressure levels
timeFrame: 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).
measure: Blood pressure variability
timeFrame: 1) 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).
measure: Blood pressure target achievement rates
timeFrame: 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.]
measure: Serum folate level
timeFrame: Serum folate levels at one year, three-year and at the end of follow-up(up to 5 years).
measure: Serum folate change
timeFrame: Serum folate changes at one year, three-year and at the end of follow-up(up to 5 years).
measure: Plasma tHcy level
timeFrame: Plasma total homocysteine levels at one year, three-year and at the end of follow-up(up to 5 years).
measure: Plasma tHcy change
timeFrame: Plasma total homocysteine changes at one year, three-year and at the end of follow-up(up to 5 years).
Locations:
city: Bengbu
country: China
facility: First Affillated Hospital of Bengbu Medical University
state: Anhui
city: Bozhou
country: China
facility: Bozhou People's Hospital
state: Anhui
city: Chizhou
country: China
facility: Chizhou People's Hospital
state: Anhui
city: Fuyang
country: China
facility: Taihe County People's Hospital
state: Anhui
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Yangjiang
country: China
facility: Yangjiang People's Hospital
state: Guangdong
city: Guiyang
country: China
facility: The Affiliated Hospital of Guizhou Medical University
state: Guizhou
city: Huaihua
country: China
facility: The First Affiliated Hospital of Hunan University of Medicine
state: Hunan
city: Loudi
country: China
facility: Loudi Central Hospital
state: Hunan
city: Lianyungang
country: China
facility: Lianyungang Oriental Hospital
state: Jiangsu
city: Lianyungang
country: China
facility: The First People's Hospital of Lianyungang
state: Jiangsu
city: Lianyungang
country: China
facility: The Second People's Hospital of Lianyungang
state: Jiangsu
city: Yancheng
country: China
facility: Yancheng First People's Hospital
state: Jiangsu
city: Ganzhou
country: China
facility: The First Affiliated Hospital of Gannan Medical University
state: Jiangxi
city: Nanchang
country: China
facility: Second Affiliated Hospital of Nanchang University
state: Jiangxi
city: Weinan
country: China
facility: Weinan Central Hospital
state: Shaanxi
city: Zaozhuang
country: China
facility: Tengzhou Central People's Hospital
state: Shandong
city: Chengdu
country: China
facility: Chengdu Fifth People's Hospital
state: Sichuan
city: Deyang
country: China
facility: Deyang People's Hospital
state: Sichuan
city: Luzhou
country: China
facility: The Affiliated Hospital of Southwest Medical University
state: Sichuan
Study officials:
affiliation: Peking University First Hospital
name: Jianping Li, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.