Folic Acid and Intensive Antihypertensive Therapy for Hypertension With CSVD

Study Overview
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Brief Summary
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The primary objectives of this trial are: 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. 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.

Detailed Description
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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.

Official Title
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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

Conditions
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Cerebral Small Vessel Diseases, Stroke

Intervention / Treatment
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* Drug: Amlodipine folic acid 5.8mg+intensive antihypertensive therapy
* Drug: Amlodipine folic acid 5.8mg+standard antihypertensive therapy
* Drug: Amlodipine+intensive antihypertensive therapy
* Drug: Amlodipine+standard antihypertensive therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 35-75 years; 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: Patients with secondary hypertension; Symptomatic intracranial and extracranial artery stenosis (stenosis ≥50%), or asymptomatic intracranial and extracranial artery stenosis (stenosis≥70%); Patients who have undergone revascularization of the heart, brain, or kidney, or other aortic stenting procedures; Any symptoms of orthostatic hypotension when measuring standing blood pressure, or if standing SBP <110mmHg; Bilateral renal artery stenosis; 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; 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); 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); Patients undergoing dialysis or with stage 4-5 chronic kidney disease, or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m²; History of epilepsy or currently using anti-epileptic medication; Pregnant and lactating women, or women planning to become pregnant; Life expectancy less than four years; Within the last month, participation in another clinical trial; Any patient determined by the researchers to be unsuitable for the present study.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Amlodipine folic acid 5.8mg+intensive antihypertensive therapy<br>This group will receive intensive antihypertensive therapy (systolic blood pressure(SBP) <130 mmHg); with amlodipine folic acid 5.8mg. | Drug: Amlodipine folic acid 5.8mg+intensive antihypertensive therapy<br>* Amlodipine folic acid tablet 5.8mg, taken daily, in the morning after waking. To achieve target blood pressure(SBP<130mmHg), this study will provide, if needed, concurrent antihypertensive medications. Patients will be asked to discontinue all prior concurrent medications. Recommended treatment options are described below: Add candesartan 4mg; Add indapamide 2.5mg; Increase dose of candesartan to 8mg; Increase dose of amlodipine to 7.5mg-10mg.<br>|
| Active Comparator: Amlodipine folic acid 5.8mg+standard antihypertensive therapy<br>This group will receive standard antihypertensive therapy (SBP: 130-140 mmHg); with amlodipine folic acid 5.8mg. | Drug: Amlodipine folic acid 5.8mg+standard antihypertensive therapy<br>* Amlodipine folic acid tablet 5.8mg, taken daily, in the morning after waking. To achieve target blood pressure (SBP:130-140mmHg), this study will provide, if needed, concurrent antihypertensive medications. Patients will be asked to discontinue all prior concurrent medications. Recommended treatment options are described below: Add candesartan 4mg; Add indapamide 2.5mg; Increase dose of candesartan to 8mg; Increase dose of amlodipine to 7.5mg-10mg.<br>|
| Active Comparator: Amlodipine+intensive antihypertensive therapy<br>This group will receive intensive antihypertensive therapy (systolic blood pressure(SBP) <130 mmHg); with amlodipine 5.0mg. | Drug: Amlodipine+intensive antihypertensive therapy<br>* Amlodipine tablet 5.8mg, taken daily, in the morning after waking. To achieve target blood pressure (SBP: 130-140 mmHg), this study will provide, if needed, concurrent antihypertensive medications. Patients will be asked to discontinue all prior concurrent medications. Recommended treatment options are described below: Add candesartan 4mg; Add indapamide 2.5mg; Increase dose of candesartan to 8mg; Increase dose of amlodipine to 7.5mg-10mg.<br>|
| Placebo Comparator: Amlodipine+standard antihypertensive therapy<br>This group will receive standard antihypertensive therapy (SBP: 130-140 mmHg); with amlodipine 5.0mg. | Drug: Amlodipine+standard antihypertensive therapy<br>* Amlodipine tablet 5.8mg, taken daily, in the morning after waking. To achieve target blood pressure (SBP: 130-140 mmHg), this study will provide, if needed, concurrent antihypertensive medications. Patients will be asked to discontinue all prior concurrent medications. Recommended treatment options are described below: Add candesartan 4mg; Add indapamide 2.5mg; Increase dose of candesartan to 8mg; Increase dose of amlodipine to 7.5mg-10mg.<br>* Other names: Standard antihypertensive therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause stroke (including fatal and non-fatal stroke) | This aims 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 stroke occurrence in cerebral small vascular disease (CSVD) patients with hypertension and elevated homocysteine (Hcy) level | 4 year after randomization | 
| Combined cardio-cerebrovascular events | This aims 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. | 4 year after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined cardio-cerebrovascular events | Secondary outcome for assessing 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 combined cardio-cerebrovascular events in cerebral small vascular disease (CSVD) patients with hypertension and elevated homocysteine (Hcy) level. | 4 year after randomization | 
| All-cause stroke (including fatal and non-fatal stroke) | Secondary outcome for assessing the effect of intensive antihypertensive therapy (SBP<130 mmHg) versus standard antihypertensive therapy (SBP 130-<140 mmHg) in reducing risk of stroke occurrence in CSVD patients with hypertension and elevated Hcy level. | 4 year after randomization | 
| Ischemic stroke | Percentage of patients within follow-up period new ischemic stroke events. | 4 year after randomization | 
| Hemorrhagic stroke | Percentage of patients within follow-up period new hemorrhagic stroke events. | 4 year after randomization | 
| Myocardial infarction | Percentage of patients within follow-up period new myocardial infarction events. | 4 year after randomization | 
| Hospitalization from heart failure | Hospitalization, or an emergency department visit requiring treatment with infusion therapy, for a clinical syndrome that presents with multiple signs and symptoms consistent with cardiac decompensation/ inadequate cardiac pump function within follow-up period. | 4 year after randomization | 
| Cardio-cerebrovascular death | Cardio-cerebrovascular death includes death caused by acute myocardial infarction (MI), sudden cardiac death, death caused by heart failure (HF), death caused by stroke, death caused by cardiovascular surgery, death caused by cardiovascular hemorrhage and other cardiovascular causes. | 4 year after randomization | 
| All-cause death | This is death due to various causes, including cardiovascular and non-vascular deaths and deaths from unknown causes. | 4 year after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebral Small Vessel Diseases, Stroke recurrence, Hypertension, Homocysteine, Folic acid