Folic Acid and Intensive Antihypertensive Therapy for Hypertension With CSVD (FAITH)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Stroke; Cerebral Small Vessel Diseases
• Intervention / Treatment: 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

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.

• Study Type: Interventional
• Enrollment (Anticipated): 15000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jinglin Mo; Phone Number: +86 18801125231; Email: mojinglin_dmu@163.com
• Study Contact Backup: Name: Anxin Wang; Phone Number: 0086-010-59978350; Email: anxin0907@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100070
      • Beijing Tiantan Hospital
      • Contact: Jinglin Mo; Phone Number: +86 18801125231; Email: mojinglin_dmu@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Amlodipine folic acid 5.8mg+intensive antihypertensive therapy; 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; 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.
Active Comparator: Amlodipine folic acid 5.8mg+standard antihypertensive therapy; 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; 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.
Active Comparator: Amlodipine+intensive antihypertensive therapy; This group will receive intensive antihypertensive therapy (systolic blood pressure(SBP) <130 mmHg); with amlodipine 5.0mg.	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: Add candesartan 4mg;; Add indapamide 2.5mg;; Increase dose of candesartan to 8mg;; Increase dose of amlodipine to 7.5mg-10mg.
Placebo Comparator: Amlodipine+standard antihypertensive therapy; This group will receive standard antihypertensive therapy (SBP: 130-140 mmHg); with amlodipine 5.0mg.	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: Add candesartan 4mg;; Add indapamide 2.5mg;; Increase dose of candesartan to 8mg;; Increase dose of amlodipine to 7.5mg-10mg.; Other Names: Standard antihypertensive therapy

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malignant tumors occurence	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 malignant tumors occurrence in cerebral small vascular disease (CSVD) patients with hypertension and elevated homocysteine (Hcy) level.	4 year after randomization
Changes in total image load score of CSVD	Changes in total image load score of CSVD	4 year after randomization
Changes in WMLs and brain volume	Changes in WMLs and brain volume	4 year after randomization
Changes in score of each single item of the grading of CSVD image load	Changes in score of each single item of the grading of CSVD image load	4 year after randomization
Changes in autonomic nervous system function and cerebral hemodynamics	Changes in autonomic nervous system function and cerebral hemodynamics	4 year after randomization
Changes in MoCA score	Changes in MoCA score	4 year after randomization

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Investigators: Principal Investigator: Yongjun Wang, Beijing Tiantan Hospital

Publications and helpful links

General 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. JAMA. 2015 Apr 7;313(13):1325-35. doi: 10.1001/jama.2015.2274.
• 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.
• 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.
• 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. Erratum In: Lancet. 2013 Aug 10;382(9891):506. Coffey, C S [aded].
• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 31, 2021
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2028

Study Registration Dates

• First Submitted: December 10, 2021
• First Submitted That Met QC Criteria: December 10, 2021
• First Posted (Actual): December 23, 2021

Study Record Updates

• Last Update Posted (Actual): December 23, 2021
• Last Update Submitted That Met QC Criteria: December 10, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Hypertension; Folic acid; Cerebral Small Vessel Diseases; Homocysteine; Stroke recurrence
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypertension; Cerebral Small Vessel Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Micronutrients; Membrane Transport Modulators; Vitamins; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Hematinics; Amlodipine; Antihypertensive Agents; Folic Acid; Vitamin B Complex
• Other Study ID Numbers: FAITH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No