NCT03472508

Brief Summary

This is a multicenter, randomized, double-blind, controlled clinical trial. It aims to investigate the effects of different doses of folic acid on lowering homocysteine (Hcy) in patients with hypertension with different genotypes of MTHFR C677T and to determine a dose-response relationship. This study consists of 3 phases: screening ( 2-10 days ), run-in period (0-2 weeks), and double-blind treatment (8 weeks). Follow-up visits will take place at the beginning of both the run-in period and the double-blind treatment period, and at the end of the 2nd, 4th, 6th, and 8th weeks. Hypertensive patients demonstrating good tolerance and adherence to angiotensin converting enzyme inhibitor (ACEI) drugs and who have already been genotyped for MTHFR C677T polymorphism may pass over the run-in period and directly enter the double-blind randomized treatment period. No medications that could affect the assessment of efficacy may be taken during any stage of the study.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
3,600

participants targeted

Target at P75+ for phase_4 hypertension

Timeline
Completed

Started Mar 2018

Geographic Reach
1 country

5 active sites

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

March 14, 2018

Completed
6 days until next milestone

Study Start

First participant enrolled

March 20, 2018

Completed
1 day until next milestone

First Posted

Study publicly available on registry

March 21, 2018

Completed
1 year until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 30, 2019

Completed
3 months until next milestone

Study Completion

Last participant's last visit for all outcomes

June 30, 2019

Completed
Last Updated

July 18, 2018

Status Verified

July 1, 2018

Enrollment Period

1 year

First QC Date

March 14, 2018

Last Update Submit

July 16, 2018

Conditions

Hypertension

Keywords

Folic acidHomocysteineMTHFR C677TRCTPrecision treatment

Outcome Measures

Primary Outcomes (1)

  • Percentage decrease in blood homocysteine levels by the end of the 8th week from baseline.

    Hcy percent decrease =（baseline Hcy - end Hcy) /baseline Hcy \*100%

    by the end of the 8th week from the baseline

Secondary Outcomes (3)

  • Magnitude of decrease in blood homocysteine by the end of the 8th week from baseline.

    by the end of the 8th week from the baseline

  • Percentage of increase in blood folate levels by the end of the 8th week from baseline.

    by the end of the 8th week from the baseline

  • Magnitude of increase in blood folate levels by the end of the 8th week from baseline.

    by the end of the 8th week from the baseline

Study Arms (8)

0 mg folic acid

SHAM COMPARATOR

Enalapril Maleate (10mg) with 0 mg folic acid

Drug: Folic AcidDrug: Enalapril

0.4mg Folic acid

ACTIVE COMPARATOR

Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.4mg)

Drug: Folic AcidDrug: Enalapril Maleate and Folic Acid Tablets (Yiye)

0.6mg Folic acid

ACTIVE COMPARATOR

Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.4mg) with 0.2 mg folic acid

Drug: Folic AcidDrug: Enalapril Maleate and Folic Acid Tablets (Yiye)

0.8mg Folic acid

ACTIVE COMPARATOR

Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg)

Drug: Folic AcidDrug: Enalapril Maleate and Folic Acid Tablets (Yiye)

1.2mg Folic acid

ACTIVE COMPARATOR

Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 0.4 mg folic acid

Drug: Folic AcidDrug: Enalapril Maleate and Folic Acid Tablets (Yiye)

1.6mg Folic acid

ACTIVE COMPARATOR

Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 0.8 mg folic acid

Drug: Folic AcidDrug: Enalapril Maleate and Folic Acid Tablets (Yiye)

2.0mg Folic acid

ACTIVE COMPARATOR

Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 1.2 mg folic acid

Drug: Folic AcidDrug: Enalapril Maleate and Folic Acid Tablets (Yiye)

2.4mg Folic acid

ACTIVE COMPARATOR

Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 1.6 mg folic acid

Drug: Folic AcidDrug: Enalapril Maleate and Folic Acid Tablets (Yiye)

Interventions

Folic AcidDRUG

Folic acid used in this study are listed products. All drugs used in the double-blind treatment period of this study will be loaded into safety capsules with the same outer appearance; all parties involved in the trial will be unaware of the contents of the capsules.

0 mg folic acid0.4mg Folic acid0.6mg Folic acid0.8mg Folic acid1.2mg Folic acid1.6mg Folic acid2.0mg Folic acid2.4mg Folic acid
Enalapril Maleate and Folic Acid Tablets (Yiye)DRUG

Enalapril Maleate and Folic Acid Tablets (Yiye) have been approved for listing by the China Food and Drug Administration. Approval number: Zhunzi H20103723.All drugs used in the double-blind treatment period of this study will be loaded into safety capsules with the same outer appearance; all parties involved in the trial will be unaware of the contents of the capsules.

0.4mg Folic acid0.6mg Folic acid0.8mg Folic acid1.2mg Folic acid1.6mg Folic acid2.0mg Folic acid2.4mg Folic acid
EnalaprilDRUG

Enalapril used in this study are listed products. All drugs used in the double-blind treatment period of this study will be loaded into safety capsules with the same outer appearance; all parties involved in the trial will be unaware of the contents of the capsules.

0 mg folic acid

Eligibility Criteria

Age45 Years+
Sexall(Gender-based eligibility)
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • （1）≥ 45 years old;
  • （2）A diagnosis or previous diagnosis of essential hypertension, including anyone currently taking antihypertensive drugs; or for those who have not taken antihypertensive drugs within the last 2 weeks, two consecutive examinations were conducted at least one day apart, and both sitting blood pressure (mean value of 3 measurements) met the following criteria: diastolic blood pressure (DBP) ≥90 mmHg or systolic blood pressure (SBP) ≥140 mmHg (the second blood pressure was measured at V1);
  • （3）If a study participant is a woman of childbearing age, she agrees to use a reliable contraceptive method during the trial;
  • （4）Voluntarily participates and has signed an informed consent form.
  • （1）Completed MTHFR C677T gene polymorphism detection in run-in period or MTHFR C677T genotype already known in advance;
  • （2）Exhibited good tolerance to enalapril and good overall medication compliance (\>80%) in run-in period or previously exhibited good tolerance and adherence to ACEI drugs in previous medication history.
  • （3）Voluntarily continues to participate in this study.

You may not qualify if:

  • Participants meeting any of the following criteria may not participate in this study:
  • （1）Women who are pregnant and/or lactating; or women who intend to conceive within a year;
  • （2）History of allergies to enalapril, folic acid or other components of the compound drug;
  • （3）History of adverse reactions or intolerance to enalapril or other ACE inhibitors, or drugs or supplements containing folic acid;
  • （4）Diagnosis or suspicion of secondary hypertension;
  • （5）Known serious medical conditions, including: Cardiovascular: patients with clinically diagnosed cardiac dysfunction (NYHA class III and above), hypertrophic obstructive cardiomyopathy, clinically significant valvular heart disease, acute coronary syndrome within the last 3 months, or percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG); or abnormal pre-enrollment ECG test results with clinically significant arrhythmias (atrial flutter, atrial fibrillation, grade II-III atrioventricular block, etc.); Digestive: a previous diagnosis of various types of viral hepatitis that are still in the active phase; abnormal pre-enrollment liver function test results (ALT, AST, GGT, TBIL, or DBIL 3 times higher than normal, ALB ≤ 30g/L); gastrectomy and/or gastrojejunostomy; gastrointestinal dysfunction; Urinary: pre-enrollment serum creatinine greater than 200μmol/L; clinical diagnosis of renal artery stenosis, isolated kidney, kidney transplantation and/or other diseases; Endocrine: type 1 diabetes or uncontrolled type 2 diabetes (fasting blood glucose above 11.1 mmol/L at pre-enrollment); previous diagnosis of hyperthyroidism and failure to correct; Respiratory: pulmonary heart disease; chronic obstructive pulmonary disease; Neuropsychiatric: recent transient ischemic attack or stroke (within the last 3 months); peripheral or severe autonomic dysfunction; mental or nervous system dysfunction, inability to express desire; known drug or alcohol dependence; Malignancy, malnutrition, hematopoietic disorders and other serious diseases.
  • （6）Significant signs of abnormalities as seen in laboratory tests or physical characteristics, which, at the discretion of the investigators, indicates that the patient is experiencing a serious illness or, may affect the observation and evaluation of the drug's efficacy or adverse events, or renders the patient unsuitable for participating in this study;
  • （7）Patients currently taking folate, B12, or B6, or any compounds containing them, who express an inability or a refusal to stop usage;
  • （8）Regular usage of folic acid supplements or compounds containing folic acid in the past 3 months;
  • （9）Participation in a clinical trial for a drug that has not yet been officially approved for marketing within one month prior to the first visit.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (5)

Anqing Research Center of Anhui Medical University Biomedical Institute

Anqing, Anhui, China

RECRUITING

Peking University First Hosptial

Beijing, China

NOT YET RECRUITING

The First People's Hospital of Lianyungang

Lianyungang, China

RECRUITING

Second Affiliated Hospital of Nanchang University

Nanchang, China

RECRUITING

People's Hospital of Rongcheng

Rongcheng, China

NOT YET RECRUITING

Related Publications (13)

  • Kjeldsen SE, Julius S, Hedner T, Hansson L. Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials. Blood Press. 2001;10(4):190-2. doi: 10.1080/08037050152669684. No abstract available.

    PMID: 11800055BACKGROUND

  • Collaboration HLT. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8.

    PMID: 9569395BACKGROUND

  • Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005 Oct;82(4):806-12. doi: 10.1093/ajcn/82.4.806.

    PMID: 16210710BACKGROUND

  • Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M, Stoll C, Alembik Y, Dott B, Czeizel AE, Gelman-Kohan Z, Scarano G, Bianca S, Ettore G, Tenconi R, Bellato S, Scala I, Mutchinick OM, Lopez MA, de Walle H, Hofstra R, Joutchenko L, Kavteladze L, Bermejo E, Martinez-Frias ML, Gallagher M, Erickson JD, Vollset SE, Mastroiacovo P, Andria G, Botto LD. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003 Aug;40(8):619-25. doi: 10.1136/jmg.40.8.619. No abstract available.

    PMID: 12920077BACKGROUND

  • Xu X, Li J, Sheng W, Liu L. Meta-analysis of genetic studies from journals published in China of ischemic stroke in the Han Chinese population. Cerebrovasc Dis. 2008;26(1):48-62. doi: 10.1159/000135653. Epub 2008 May 30.

    PMID: 18511872BACKGROUND

  • Dong Q, Tang G, He M, Cai Y, Cai Y, Xing H, Sun L, Li J, Zhang Y, Fan F, Wang B, Sun N, Liu L, Xu X, Hou F, Shen H, Xu X, Huo Y. Methylenetetrahydrofolate reductase C677T polymorphism is associated with estimated glomerular filtration rate in hypertensive Chinese males. BMC Med Genet. 2012 Aug 16;13:74. doi: 10.1186/1471-2350-13-74.

    PMID: 22897803BACKGROUND

  • Huang X, Li Y, Li P, Li J, Bao H, Zhang Y, Wang B, Sun N, Wang J, He M, Yin D, Tang G, Chen Y, Cui Y, Huang Y, Hou FF, Qin X, Huo Y, Cheng X. Association between percent decline in serum total homocysteine and risk of first stroke. Neurology. 2017 Nov 14;89(20):2101-2107. doi: 10.1212/WNL.0000000000004648. Epub 2017 Oct 13.

    PMID: 29030456BACKGROUND

  • Qin X, Li J, Cui Y, Liu Z, Zhao Z, Ge J, Guan D, Hu J, Wang Y, Zhang F, Xu X, Wang X, Xu X, Huo Y. MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults. Nutr J. 2012 Jan 10;11:2. doi: 10.1186/1475-2891-11-2.

    PMID: 22230384RESULT

  • Qin X, Li J, Cui Y, Liu Z, Zhao Z, Ge J, Guan D, Hu J, Wang Y, Zhang F, Xu X, Wang X, Xu X, Huo Y. Effect of folic acid intervention on the change of serum folate level in hypertensive Chinese adults: do methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms affect therapeutic responses? Pharmacogenet Genomics. 2012 Jun;22(6):421-8. doi: 10.1097/FPC.0b013e32834ac5e8.

    PMID: 21869730RESULT

  • Qin X, Li J, Zhang Y, Ma W, Fan F, Wang B, Xing H, Tang G, Wang X, Xu X, Xu X, Huo Y. Prevalence and associated factors of diabetes and impaired fasting glucose in Chinese hypertensive adults aged 45 to 75 years. PLoS One. 2012;7(8):e42538. doi: 10.1371/journal.pone.0042538. Epub 2012 Aug 3.

    PMID: 22880024RESULT

  • 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.

    PMID: 25771069RESULT

  • Huang X, Bao H, Ding C, Li J, Cao T, Liu L, Wei Y, Zhou Z, Zhang N, Song Y, Chen P, Jiang C, Xie L, Qin X, Zhang Y, Li J, Sun N, Tang G, Wang X, Wang H, Huo Y, Cheng X; Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy) Trial Investigators. Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy). Eur J Nutr. 2024 Aug;63(5):1513-1528. doi: 10.1007/s00394-024-03344-8. Epub 2024 Mar 13.

    PMID: 38478042DERIVED

  • Chen P, Tang L, Song Y, Wang B, Qin X, Zhang N, Wei Y, Xu X, Zhou Z, He Q, Liu L, Siddiqi SM, Huang X, Cheng X, Tang G, Duan Y, Zhou H, Jiang J, Li S. Association of folic acid dosage with circulating unmetabolized folic acid in Chinese adults with H-type hypertension: a multicenter, double-blind, randomized controlled trial. Front Nutr. 2023 Sep 14;10:1191610. doi: 10.3389/fnut.2023.1191610. eCollection 2023.

    PMID: 37781132DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Folic AcidEnalapril

Condition Hierarchy (Ancestors)

Vascular DiseasesCardiovascular Diseases

Intervention Hierarchy (Ancestors)

PterinsPteridinesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-RingHeterocyclic CompoundsDipeptidesOligopeptidesPeptidesAmino Acids, Peptides, and Proteins

Study Officials

  • Xiaoshu Cheng, MD

    Second Affiliated Hospital of Nanchang University

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Minqing Tian, PhD

CONTACT

86-18818680849tianminqing@163.com

Study Design

Study Type
interventional
Phase
phase 4
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, INVESTIGATOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Model Details: Multicenter, randomized, double-blind, controlled clinical trial
Sponsor Type
INDUSTRY
Responsible Party
SPONSOR

Study Record Dates

First Submitted

March 14, 2018

First Posted

March 21, 2018

Study Start

March 20, 2018

Primary Completion

March 30, 2019

Study Completion

June 30, 2019

Last Updated

July 18, 2018

Record last verified: 2018-07

Locations

CN(5)