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

Phase 4

Recruiting

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

• Registration Number: NCT04974138
• Lead Sponsor: Shenzhen Ausa Pharmed Co.,Ltd

Brief Summary

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.

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 Timeline

• Study First Submitted: 2021-07-13
• Study First Submitted QC: 2021-07-13
• Study First Posted: 2021-07-23
• Study Start: 2024-08-22
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-24
• Last Update Posted: 2025-02-26
• Primary Completion: 2030-06-30
• Study Completion: 2030-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 32000

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CC with amlodipine 5mg/d	Amlodipine besylate	For subjects with the MTHFR CC genotype, amlodipine (5mg) + amlodipine-folic acid (dummy), once daily, taken orally in the morning after waking-up.
CC with amlodipine 5mg/d	Amlodipine-folic acid placebos	For subjects with the MTHFR CC genotype, amlodipine (5mg) + amlodipine-folic acid (dummy), once daily, taken orally in the morning after waking-up.
CC with amlodipine folic acid 5.8mg/d	Amlodipine besylate and folic acid	For subjects with the MTHFR CC genotype, amlodipine-folic acid (5.8mg) + amlodipine (dummy), once daily, taken orally in the morning after waking-up.
CC with amlodipine folic acid 5.8mg/d	Amlodipine placebos	For subjects with the MTHFR CC genotype, amlodipine-folic acid (5.8mg) + amlodipine (dummy), once daily, taken orally in the morning after waking-up.
CT with amlodipine 5mg/d	Amlodipine besylate	For subjects with the MTHFR CT genotype, amlodipine (5mg) + amlodipine-folic acid (dummy), once daily, taken orally in the morning after waking-up.
CT with amlodipine 5mg/d	Amlodipine-folic acid placebos	For subjects with the MTHFR CT genotype, amlodipine (5mg) + amlodipine-folic acid (dummy), once daily, taken orally in the morning after waking-up.
CT with amlodipine folic acid 5.8mg/d	Amlodipine besylate and folic acid	For subjects with the MTHFR CT genotype, amlodipine-folic acid (5.8mg) + amlodipine (dummy), once daily, taken orally in the morning after waking-up.
CT with amlodipine folic acid 5.8mg/d	Amlodipine placebos	For subjects with the MTHFR CT genotype, amlodipine-folic acid (5.8mg) + amlodipine (dummy), once daily, taken orally in the morning after waking-up.

Primary Outcome Measures

Name	Time	Method
First ischemic stroke	By the end of the fifth year from baseline	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.

Secondary Outcome Measures

Name	Time	Method
First ischemic stroke (for refined treatment group comparisons)	By the end of the fifth year from baseline	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
First stroke (ischemic and hemorrhagic)	By the end of the fifth year from baseline	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
Composite cardiovascular endpoint (first non-fatal stroke, first non-fatal myocardial infarction, cardiovascular death)	By the end of the fifth year from baseline	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
Kidney outcomes	By the end of the fifth year from baseline	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
First hemorrhagic stroke	By the end of the fifth year from baseline	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
First myocardial infarction	By the end of the fifth year from baseline	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
First coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI])	By the end of the fifth year from baseline	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
Cardiovascular death	By the end of the fifth year from baseline	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

Trial Locations

Locations (20)

Deyang People's Hospital; 🇨🇳 Deyang, Sichuan, China

First Affiliated Hospital of Bengbu Medical University; 🇨🇳 Bengbu, Anhui, China

Bozhou; 🇨🇳 Bozhou, Anhui, China

Chizhou People's Hospital; 🇨🇳 Chizhou, Anhui, China

Taihe County People's Hospital; 🇨🇳 Fuyang, Anhui, China

Peking University First Hospital; 🇨🇳 Beijing, Beijing, China

Yangjiang People's Hospital; 🇨🇳 Yangjiang, Guangdong, China

The Affiliated Hospital Of Guizhou Medical University; 🇨🇳 Guiyang, Guizhou, China

The First Affiliated Hospital of Hunan University of Medicine; 🇨🇳 Huaihua, Hunan, China

Loudi Central Hospital; 🇨🇳 Loudi, Hunan, China

Lianyungang Oriental Hospital; 🇨🇳 Lianyungang, Jiangsu, China

The First People's Hospital of Lianyungang; 🇨🇳 Lianyungang, Jiangsu, China

The Second People's Hospital of Lianyungang; 🇨🇳 Lianyungang, Jiangsu, China

Yancheng First People's Hospital; 🇨🇳 Yancheng, Jiangsu, China

The First Affiliated Hospital of Gannan Medical University,; 🇨🇳 Ganzhou, Jiangxi, China

Second Affiliated Hospital of Nanchang University; 🇨🇳 Nanchang, Jiangxi, China

Weinan Central Hospital; 🇨🇳 Weinan, Shaanxi, China

Tengzhou Central People's Hospital; 🇨🇳 Zaozhuang, Shandong, China

Chengdu Fifth People's Hospital; 🇨🇳 Chengdu, Sichuan, China

The Affiliated Hospital of Southwest Medical University; 🇨🇳 Luzhou, Sichuan, China