Folic Acid Supplementation in Calcific Aortic Valve Disease

Effect of Folic Acid Supplementation in Patient's Calcific Aortic Valve Disease With Mild Aortic Valve Stenosis

This is a prospective, randomized, comparative, clinical trial conducted by Wuhan Union Hospital that aims to evaluate the efficacy and safety of folic acid compared to placebo in patients with calcific aortic valve disease with mild aortic valve stenosis.

Study Overview

• Status: Not yet recruiting
• Conditions: Aortic Valve Stenosis; Calcification of Aortic Valve
• Intervention / Treatment: Drug: Folic Acid Oral Tablet; Dietary supplement: Placebo

Detailed Description

Folic acid is involved in important physiological activities in the body such as DNA synthesis, cell division and growth and development. Recent studies have shown that folic acid may also have a positive effect on cardiovascular system health. Aortic valve calcification is a cardiovascular disease whose incidence increases progressively with age. Early studies suggest that folic acid may slow the progression of aortic valve calcification by inhibiting cell calcification and promoting calcium deposition. Participants were randomized into two groups: one group was given oral folic acid treatment and the other group was given placebo control. Patients in both groups were observed for aortic valve calcification during the follow-up period, and changes in aortic valve thickness, degree of calcification, and flow were recorded by cardiac ultrasonography, while the incidence of cardiovascular events and adverse effects were assessed.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Fei Li, MD; Phone Number: +86 15972969897; Email: lifei_union@hust.edu.cn
• Study Contact Backup: Name: Li Xu, MD; Phone Number: +86 15387030212; Email: unionxuli@hust.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female adult ≥ 35 years of age at the time of recruiting.
• Subject has calcific aortic valve disease with mild to moderate aortic valve stenosis as defined by Doppler echocardiography results: Aortic Valve mean pressure gradient between 10-30 mmHg and Aortic Valve Area ≥ 1.2 and ≤ 2.0 cm2 on transthoracic echocardiography within 2 weeks prior to randomization and Cardiac Compute Tomography (CT) test results: aortic valve calcium score (Agatston score) ≥ 200 AU at baseline cardiac CT within 1 month prior to randomization
• Subject provides written informed consent prior to initiation of any study procedures.
• Subject understands and agrees to comply with planned study procedures.

Exclusion Criteria:

• Subject has concomitant moderate or severe mitral or tricuspid valve disease.
• Subject has left ventricular ejection fraction < 50%.
• Subject previous history of aortic valve surgery, pancreatitis, malignant tumor, drug or alcohol abuse.
• Subjects whose alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 times the upper limit of normal range.
• Subjects who cannot undergo Cardiac CT.
• Pregnant or lactating women.
• Consideration by the investigator, for safety reasons, that the subject is an unsuitable candidate to receive study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug group 1; Dietary Supplement: Folic acid 2.5 mg/day	Drug: Folic Acid Oral Tablet; Dietary Supplement: Folic acid 2.5mg/day
Placebo Comparator: Control group 2; Dietary Supplement: Placebo	Dietary supplement: Placebo; Dietary Supplement: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aortic valve calcification	Aortic valve calcification as measured by change from baseline in Agatston arbitrary unit (AU) using cardiac computed tomography (CT) at 104 weeks	104 weeks
overall survival	overall survival (OS)	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-major adverse cardiovascular events	Time-to-major adverse cardiovascular events of cardiac death, non- fatal myocardial infarction, heart failure hospitalization and stroke	104 weeks
Aortic valve calcification	Change in aortic valve calcification as measured by Agatston AU using cardiac computed tomography (CT) at week 52	at week 52
Change in aortic valve stenosis severity	Change in aortic valve stenosis severity as measured by peak transaortic velocity using echocardiography at week 104 as compared to baseline	at week 104

Collaborators and Investigators

• Sponsor: Wuhan Union Hospital, China

Publications and helpful links

General Publications

• Gao L, Chalupsky K, Stefani E, Cai H. Mechanistic insights into folic acid-dependent vascular protection: dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: a novel HPLC-based fluorescent assay for DHFR activity. J Mol Cell Cardiol. 2009 Dec;47(6):752-60. doi: 10.1016/j.yjmcc.2009.07.025. Epub 2009 Aug 3.
• Moens AL, Claeys MJ, Wuyts FL, Goovaerts I, Van Hertbruggen E, Wendelen LC, Van Hoof VO, Vrints CJ. Effect of folic acid on endothelial function following acute myocardial infarction. Am J Cardiol. 2007 Feb 15;99(4):476-81. doi: 10.1016/j.amjcard.2006.08.057. Epub 2006 Dec 28.
• Shirodaria C, Antoniades C, Lee J, Jackson CE, Robson MD, Francis JM, Moat SJ, Ratnatunga C, Pillai R, Refsum H, Neubauer S, Channon KM. Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease. Circulation. 2007 May 1;115(17):2262-70. doi: 10.1161/CIRCULATIONAHA.106.679084. Epub 2007 Apr 9.
• Stanger O. Physiology of folic acid in health and disease. Curr Drug Metab. 2002 Apr;3(2):211-23. doi: 10.2174/1389200024605163.
• Gao L, Siu KL, Chalupsky K, Nguyen A, Chen P, Weintraub NL, Galis Z, Cai H. Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid. Hypertension. 2012 Jan;59(1):158-66. doi: 10.1161/HYPERTENSIONAHA.111.181644. Epub 2011 Nov 14.

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2023
• Primary Completion (Anticipated): July 1, 2025
• Study Completion (Anticipated): July 1, 2028

Study Registration Dates

• First Submitted: May 4, 2023
• First Submitted That Met QC Criteria: May 16, 2023
• First Posted (Actual): May 17, 2023

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Aortic Valve Stenosis; Folic Acid; Calcification of Aortic Valve
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Pathological Conditions, Anatomical; Heart Valve Diseases; Ventricular Outflow Obstruction; Calcium Metabolism Disorders; Aortic Valve Stenosis; Constriction, Pathologic; Aortic Valve Disease; Calcinosis; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Folic Acid
• Other Study ID Numbers: WUHFACAVD01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: we would like to share individual participant data with other researchers 1 years after the trial completely finished
• IPD Sharing Access Criteria: All data should only be used for academic research.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes