Clinical trial NCT05169021: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Cerebral Small Vessel Diseases
Stroke
Keywords: Cerebral Small Vessel Diseases
Stroke recurrence
Hypertension
Homocysteine
Folic acid
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
First posted: 2021-12-23
Enrollment: 15000
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: All-cause stroke (including fatal and non-fatal stroke)
timeFrame: 4 year after randomization
measure: Combined cardio-cerebrovascular events
timeFrame: 4 year after randomization
Secondary outcomes:
measure: Combined cardio-cerebrovascular events
timeFrame: 4 year after randomization
measure: All-cause stroke (including fatal and non-fatal stroke)
timeFrame: 4 year after randomization
measure: Ischemic stroke
timeFrame: 4 year after randomization
measure: Hemorrhagic stroke
timeFrame: 4 year after randomization
measure: Myocardial infarction
timeFrame: 4 year after randomization
measure: Hospitalization from heart failure
timeFrame: 4 year after randomization
measure: Cardio-cerebrovascular death
timeFrame: 4 year after randomization
measure: All-cause death
timeFrame: 4 year after randomization
Other outcomes:
measure: Malignant tumors occurence
timeFrame: 4 year after randomization
measure: Changes in total image load score of CSVD
timeFrame: 4 year after randomization
measure: Changes in WMLs and brain volume
timeFrame: 4 year after randomization
measure: Changes in score of each single item of the grading of CSVD image load
timeFrame: 4 year after randomization
measure: Changes in autonomic nervous system function and cerebral hemodynamics
timeFrame: 4 year after randomization
measure: Changes in MoCA score
timeFrame: 4 year after randomization
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital
state: Beijing
Study officials:
affiliation: Beijing Tiantan Hospital
name: Yongjun Wang
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. JAMA. 2015 Apr 7;313(13):1325-35. doi: 10.1001/jama.2015.2274.
citation: 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.
citation: 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.
citation: 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.
citation: 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.