Folic Acid and Intensive Antihypertensive Therapy for Hypertension With CSVD

Folic Acid and Intensive Antihypertensive Therapy for Cerebrovascular and Cardiovascular Events Prevention Among Patients With Hypertension and Cerebral Small Vascular Diseases (FAITH)----A Multicenter, Randomized, Controlled, Open-label, 2x2 Factorial, Blinded End-point Trial

The primary objectives of this trial are:

1. Efficacy evaluation of amlodipine folic acid tablets:

   To assess the effects of amlodipine folic acid tablets 5.8 mg (5 mg amlodipine + 0.8 mg folic acid)versus amlodipine tablets 5 mg in preventing all-cause stroke in cerebral small vascular disease (CSVD) patients with hypertension and elevated homocysteine (Hcy) level.

2. Intensive Antihypertensive Therapy:

To assess the effect of intensive antihypertensive therapy (SBP<130 mmHg) versus standard antihypertensive therapy (SBP 130-<140 mmHg) in reducing risk of combined cardio-cerebrovascular events in CSVD patients with hypertension and elevated Hcy level, using two basic anti-hypertensive drugs, amlodipine tablets 5 mg or amlodipine folic acid tablets 5.8 mg.

Hypertension is highly prevalent risk factor for stroke, particularly for stroke associated with CSVD. Blood pressure (BP) lowering has been considered an important measure for preventing stroke and progression of CSVD. Moreover, uncertainty remains regarding the efficacy of folic acid therapy for secondary prevention of stroke because of limited and inconsistent data. We propose to conduct a randomized, double-blind, placebo-controlled, multicenter, 2×2 factorial designed clinical trial to test the primary hypothesis that 1) whether amlodipine folic acid is more effective than amlodipine in reducing the risk of all-cause stroke (including fatal and non-fatal stroke) over a follow-up period among patients with CSVD. 2) whether an intensive treatment strategy (a systolic BP target of <130mmHg) is more effective than a standard treatment strategy (a systolic BP target of 130-140mmHg) in reducing the risk of combined cardio-cerebrovascular events.

Both Intention-to-treat Analysis (ITT) and Per-protocol set (PPS) were used for analysis.

We will use Kaplan-Meier estimates of the cumulative risk of stroke (ischemic or hemorrhagic) event and combined cardio-cerebrovascular events during follow-up period, with hazards ratios and 95% CI calculated using Cox proportional hazards methods and the log-rank test to evaluate the treatment effect. All statistics will be 2-sided with P<0.05 considered significant, accounting for interim analyses.

All patients who received study drugs and with at least one safety follow-up record will be included in the safety population. The data for safety evaluation included adverse reactions observed during the trial and changes in laboratory data before and after treatment.

Inclusion Criteria:

1. Age 35-75 years;
2. Meets any of the following criteria:

1) Lacunar infarction occurring within the period of seven days up to one year post-infarction, diagnosed by head MRI/CT (meeting modified Fisher criteria*); 2）Head MRI indicating white matter hyperintensity, 4≥Fazekas score*≥2; 3）Head MRI indicating white matter hyperintensity, Fazekas=1, combined with old subcortical vascular lacunar infarction;

• For modified Fisher criteria and Fazekas score, see FAITH main study appendix 1 and appendix 6).

  3. Medical recorded history of hypertension. Systolic blood pressure SBP: 130-180 mm Hg on 0 or 1 medication SBP: 130-170 mm Hg on up to 2 medications SBP: 130-160 mm Hg on up to 3 medications. 4. mRS score ≤2; 5. Serum Hcy ≥10 µmol/L or MTHFR 677 TT genotype; 6. Signed informed consent form.

Exclusion Criteria:

1. Patients with secondary hypertension;
2. Symptomatic intracranial and extracranial artery stenosis (stenosis ≥50%), or asymptomatic intracranial and extracranial artery stenosis (stenosis≥70%);
3. Patients who have undergone revascularization of the heart, brain, or kidney, or other aortic stenting procedures;
4. Any symptoms of orthostatic hypotension when measuring standing blood pressure, or if standing SBP <110mmHg;
5. Bilateral renal artery stenosis;
6. Patients who have previously taken candesartan or other angiotensin receptor antagonist (ARB) type medication, indapamide or other similar diuretic type medication, or any medication or health product containing folic acid, and reported adverse reactions;
7. Patients who have indicators for specific antihypertensive medications (e.g. β-blockers after acute myocardial infarction, RAS blockers for prevention of cardiovascular disease, α-blockers for treatment of benign prostate hyperplasia);
8. Within the last three months, regular usage of vitamin supplements containing folic acid, B6, or B12, or usage of folic acid antagonists (e.g. methotrexate);
9. Patients undergoing dialysis or with stage 4-5 chronic kidney disease, or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m²;
10. History of epilepsy or currently using anti-epileptic medication;
11. Pregnant and lactating women, or women planning to become pregnant;
12. Life expectancy less than four years;
13. Within the last month, participation in another clinical trial;
14. Any patient determined by the researchers to be unsuitable for the present study.