Elevated Plasma Homocysteine (Hcy≥10µmol/L), Hypertension, Insufficient Plasma Folate Levels (<12ng/mL), MTHFR 677 CC or CT Genotype
Conditions
Keywords
Folic acid, Homocysteine, MTHFR C677T genotype, Randomized controlled trial, Ischemic stroke
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.
Interventions
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).
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).
DRUGAmlodipine placebos
An amlodipine placebo is a dummy pill of an amlodipine tablet with an identical appearance.
DRUGAmlodipine-folic acid placebos
An Amlodipine folic acid placebo is a dummy pill of an amlodipine folic acid tablet with an identical appearance.
Sponsors
Peking University First Hospital
Second Affiliated Hospital of Nanchang University
The First People's Hospital of Lianyungang
The Affiliated Hospital Of Guizhou Medical University
Lianyungang Oriental Hospital
Tengzhou Central People's Hospital
The First Affiliated Hospital of Bengbu Medical University
Shenzhen Prospective Medical Technology Co., LTD
Weinan Central Hospital
The First Affiliated Hospital of HuNan University of Medicine
Loudi Central Hospital
Yancheng First People's Hospital
TAIHE country people's hospital
First Affiliated Hospital of Gannan Medical University
Yangjiang People's Hospital
Deyang People's Hospital
Bozhou people's hospital
Lianyungang Second People's Hospital
The Affiliated Hospital Of Southwest Medical University
Chengdu Fifth People's Hospital
Chizhou people's hospital
Shenzhen Ausa Pharmed Co.,Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Multicenter, randomized, controlled, double-blind, double-dummy clinical trial
Eligibility
Sex/Gender
ALL
Age
45 Years to 74 Years
Healthy volunteers
No
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.).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Malignant tumors | By the end of the fifth year from baseline | 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 |
| All-cause mortality | By the end of the fifth year from baseline | 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 |
| 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). | 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 |
| Blood pressure variability | 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). | 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 |
| Blood pressure target achievement rates | 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.] | 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 |
| Serum folate level | Serum folate levels at one year, three-year and at the end of follow-up(up to 5 years). | 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 change | Serum folate changes at one year, three-year and at the end of follow-up(up to 5 years). | 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 |
| Plasma tHcy level | Plasma total homocysteine levels at one year, three-year and at the end of follow-up(up to 5 years). | 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 tHcy change | Plasma total homocysteine changes at one year, three-year and at the end of follow-up(up to 5 years). | 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 |
Countries
China
Contacts
Primary ContactMinqing Tian, PhD
Outcome results
None listed