Folic Acid and Intensive Antihypertensive Therapy for Hypertension With CSVD

Official title

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

Overview

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.

Detailed description

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.

Interventions

• Drug Amlodipine folic acid 5.8mg+intensive antihypertensive therapy
  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: 1. Add candesartan 4mg; 2. Add indapamide 2.5mg; 3. Increase dose of candesartan to 8mg; 4. Increase dose of amlodipine to 7.5mg-10mg.
• Drug Amlodipine folic acid 5.8mg+standard antihypertensive therapy
  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: 1. Add candesartan 4mg; 2. Add indapamide 2.5mg; 3. Increase dose of candesartan to 8mg; 4. Increase dose of amlodipine to 7.5mg-10mg.
• Drug Amlodipine+intensive antihypertensive therapy
  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: 1. Add candesartan 4mg; 2. Add indapamide 2.5mg; 3. Increase dose of candesartan to 8mg; 4. Increase dose of amlodipine to 7.5mg-10mg.
• Drug Amlodipine+standard antihypertensive therapy
  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: 1. Add candesartan 4mg; 2. Add indapamide 2.5mg; 3. Increase dose of candesartan to 8mg; 4. Increase dose of amlodipine to 7.5mg-10mg.

Primary outcome measures

• All-cause stroke (including fatal and non-fatal stroke) [Time frame: 4 year after randomization]
• Combined cardio-cerebrovascular events [Time frame: 4 year after randomization]

Secondary outcome measures (8)

• Combined cardio-cerebrovascular events [Time frame: 4 year after randomization]
• All-cause stroke (including fatal and non-fatal stroke) [Time frame: 4 year after randomization]
• Ischemic stroke [Time frame: 4 year after randomization]
• Hemorrhagic stroke [Time frame: 4 year after randomization]
• Myocardial infarction [Time frame: 4 year after randomization]
• Hospitalization from heart failure [Time frame: 4 year after randomization]
• Cardio-cerebrovascular death [Time frame: 4 year after randomization]
• All-cause death [Time frame: 4 year after randomization]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

China · 1 center

• Beijing Tiantan Hospital — Beijing

Publications

• 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. J PMID 25771069
• Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004 Feb 4;291(5):565-75. doi: 10.1001/jama.291.5.565. PMID 14762035
• VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 2010 Sep;9(9):855-65. doi: 10.1016/S1474-4422(10)70187-3. Epub 2010 Aug 3. PMID 20688574
• SPS3 Study Group; Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013 Aug 10;382(9891):507-15. doi: 10.1016/S0140-6736(13)60852-1. Epub 2013 May 29. PMID 23726159
• Croall ID, Tozer DJ, Moynihan B, Khan U, O'Brien JT, Morris RG, Cambridge VC, Barrick TR, Blamire AM, Ford GA, Markus HS; PRESERVE Study Team. Effect of Standard vs Intensive Blood Pressure Control on Cerebral Blood Flow in Small Vessel Disease: The PRESERVE Randomized Clinical Trial. JAMA Neurol. 2018 Jun 1;75(6):720-727. doi: 10.1001/jamaneurol.2017.5153. PMID 29507944

Identifiers

NCT: NCT05169021 · FAITH

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗