HypertensionPhase 4NCT03472508

H-Type Hypertension Precision Medicine Trial

A Phase 4 study testing Folic Acid, Enalapril Maleate and Folic Acid Tablets (Yiye) and Enalapril in people with Hypertension, run by Shenzhen Ausa Pharmed Co.,Ltd at 5 sites in China.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 45 years and older
Conditions the study is for: Hypertension
What is being tested?: Folic Acid, Enalapril Maleate and Folic Acid Tablets (Yiye) and Enalapril
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 3,600 participants
Where: 5 sitesChina
Study dates: 20 Mar 2018to 30 Jun 2019
Phase: Phase 4
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 45 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

（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.

Who cannot join

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.

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（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.

Trial locations and contacts

5 sites in 1 country.

Minqing Tian, PhD contact

86-18818680849

tianminqing@163.com

City, postcode or hospital

Sites recruiting now only

5 sites in 1 country

China5 sites, 5 recruiting

Anqing Research Center of Anhui Medical University Biomedical Institute
Anqing, Anhui
Qing Jiang, MD
Recruiting
Peking University First Hosptial
Beijing
Jianping Li, MD
Jianping Li, MD
Not yet recruiting
The First People's Hospital of Lianyungang
Lianyungang
Xiaoming Li, MD
Xiaoming Li, MD
Recruiting
Second Affiliated Hospital of Nanchang University
Nanchang
Xiaoshu Cheng, MD
Xiaoshu Cheng, MD
Recruiting
People's Hospital of Rongcheng
Rongcheng
Chongqian Fang, MD
Chongqian Fang, MD
Not yet recruiting

Other trials in China

About this study

Official title: A Randomized, Double-Blind, Controlled Trial on the Homocysteine-Lowering Effects of Different Doses of Folic Acid Among Patients With Hypertension According to Methylenetetrahydrofolate Reductase C677T Genotypes

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.

Read the detailed description

Phase I: Screening（V0）

Phase I takes place for about 2-10 days. The purpose is to obtain informed consent and make a preliminary assessment of the patient.

At the first screening visit (V0), or prior to the official treatment visit, a clinical examination will be performed to determine the patient's clinical diagnosis and to determine eligibility for inclusion in the study. General demographic information and questions related to the inclusion/exclusion criteria of this study will be obtained. Additionally, this will be the time to discuss the impact of participant vacation/travel plans on adherence and compliance with the trial protocol.

Before carrying out any research procedures, the purpose of the study and study procedures will be explained and the participant's informed consent will be obtained.

Clinical Diagnosis and Assessment: Prior to the start of the Run-in Period, baseline data and efficacy evaluation data will be collected according to the study flow chart; blood and urine samples will also be collected.

Blood Pressure Measurement: A unified electronic sphygmomanometer blood pressure measurement will be obtained. Participants will be prohibited from smoking, drinking coffee or tea, and urinating 30 minutes prior. Before taking the measurement, participants will be asked to sit quietly for at least 5 minutes prior; the participant will then be asked to assume a sitting position, with both feet flat on the ground and the upper right arm exposed and at the same height as the heart. After measurement, the sphygmomanometer will display the blood pressure and pulse. The average of 3 consecutive measurements with 1-2 minutes between each measurement will be taken and recorded. The median of 3 pulse measurements will also be recorded.

Laboratory Tests: Female participants of childbearing age must undergo a pregnancy test prior to the run-in period. Based on clinical indications, the investigator may also decide to conduct a pregnancy test at any time throughout the trial as needed. All participants will be asked to complete the following laboratory tests: 12-lead ECG, urinalysis, blood biochemistry, folate, and Hcy assessment during the screening period. All results will be obtained prior to the run-in period visit.

Phase Ⅱ: Run-in Period (V1-V2)

All eligible patients will begin a treatment of enalapril (10mg/d) for a 0 to 2-week open induction period, during which time other antihypertensive drugs may also be concurrently used. MTHFR C677T genotype will also be determined during this phase. The primary purpose of this phase is to assess participant compliance to the enalapril treatment regimen as well as to observe the participant's tolerance to enalapril, so as to avoid including those participants with poor compliance or intolerance to enalapril to the double-blind treatment phase.

Newly diagnosed hypertensives should be given enalapril during the run-in period and can be given other antihypertensive drugs at the clinician's discretion. For hypertensive patients currently using medication, if not currently using enalapril, the clinician should, based on the patient's medical condition, add or switch the patient's medication to enalapril.

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.

Phase Ⅲ: Double-Blind Treatment (V2-V6)

The third phase consists of 8 weeks of a randomized, double-blind treatment. Patients who remain eligible for participation in the study will first be stratified by gender and MTHFR C677T genotype (CC, CT, TT), for a total of 6 strata at the start of V2. Each of the 6 strata will then be randomized into 8 treatment groups: either enalapril only (10mg), or one of the other 7 treatment combinations with various doses of folic acid. During the 8-week double-blind treatment period, other antihypertensive drugs can be combined with the treatment drug to achieve blood pressure control; the patient will be followed-up every 2 weeks during the treatment period, and the treatment drug will be distributed at each visit. During this period, participants should continue to avoid taking medications that may interfere with the evaluation of treatment efficacy.

For participants who complete the run-in period and are eligible to remain in the study, a randomized treatment allocation list will be generated using a stratified, block-wise, randomized approach by MTHFR C677T genotype and gender. This list will assign a unique study ID to every study participant. The ID corresponds to a specific treatment allocation; this ID assignment determines the treatment type the participant will receive.

This study will use a two-level blinding procedure. The first level of blinding will generate a randomized sequence table corresponding each study ID to one of the eight different treatment groups. Each treatment will be given a treatment group code (from a to h) so that the actual treatment cannot be identified from this table. The second level of blinding will denote the type of treatment that corresponds to each of the eight different coded treatment groups (a through h) that were generated from the first level of blinding. The randomized ID's will be generated by a statistical analysis group; the blinding program and all electronic documents regarding the level one and two blinding will be sealed in separate envelopes and protected by the sponsor. The seal cannot be broken before the trial officially undergoes the unblinding process. In addition, the research drug management center will maintain a copy of the treatment allocation list and will be responsible for encoding the treatment drugs and dispensing the medications to the participants based on the treatment allocation list.

Conditions: Hypertension
Being tested: Folic Acid, Enalapril Maleate and Folic Acid Tablets (Yiye), Enalapril
Keywords: Folic acid, Homocysteine, MTHFR C677T, RCT, Precision treatment
Medical subject headings: Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

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.
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.
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.

Study groups in NCT03472508
Study group	Role	What they receive
0 mg folic acid	Sham comparator	Enalapril Maleate (10mg) with 0 mg folic acid Receives: Drug: Folic Acid; Drug: Enalapril
0.4mg Folic acid	Active comparator	Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.4mg) Receives: Drug: Folic Acid; Drug: 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 Receives: Drug: Folic Acid; Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)
0.8mg Folic acid	Active comparator	Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) Receives: Drug: Folic Acid; Drug: 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 Receives: Drug: Folic Acid; Drug: 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 Receives: Drug: Folic Acid; Drug: 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 Receives: Drug: Folic Acid; Drug: 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 Receives: Drug: Folic Acid; Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)

What is being measured

The primary outcome is the main question the study is designed to answer.

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%
Measured: 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.
Absolute Hcy reduction (μmol/L) = baseline Hcy - end Hcy
Measured: 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.
Folate increase rate=(end folate- baseline folate)/baseline folate *100%
folate increase magnitude= end folate - baseline folate
Measured: 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.
Absolute folate reduction (μmol/L)= baseline folate - end folate
Measured: by the end of the 8th week from the baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

20 Mar 201830 Jun 2019

First posted21 Mar 2018
Study start20 Mar 2018
Primary completion30 Mar 2019 (estimated)
Study completion30 Jun 2019 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (13)Papers the sponsor has linked to this study.
Other trials for HypertensionStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: Multicenter, randomized, double-blind, controlled clinical trial
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 3,600 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03472508
Sponsor's protocol ID: ausa1801
Status last verified: Jul 2018
First submitted: 14 Mar 2018
Last updated: 18 Jul 2018
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Undecided

Publications

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.
PubMed 11800055
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.
PubMed 9569395
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.
PubMed 16210710
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.
PubMed 12920077
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.
PubMed 18511872
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.
PubMed 22897803
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.
PubMed 29030456
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.
PubMed 22230384
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.
PubMed 21869730
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.
PubMed 22880024
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.
PubMed 25771069
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.
PubMed 38478042
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.
PubMed 37781132

Want to know more?

Minqing Tian, PhD

86-18818680849

tianminqing@163.com

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 18 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Randomized, Double-Blind, Controlled Trial on the Homocysteine-Lowering Effects of Different Doses of Folic Acid Among Patients With Hypertension According to Methylenetetrahydrofolate Reductase C677T Genotypes
ClinicalTrials.gov ID: NCT03472508
Acronym / sponsor ID: ausa1801
Conditions: Hypertension
Keywords: Folic acid, Homocysteine, MTHFR C677T, RCT, Precision treatment
Phase: Phase 4
Study type: Interventional
Recruitment status: Unknown status
Enrolment: 3,600 participants (estimated)
Lead sponsor: Shenzhen Ausa Pharmed Co.,LtdIndustry (pharma, biotech, devices)
Collaborators: Second Affiliated Hospital of Nanchang University, Shenzhen Evergreen Medical Institute, Nanfang Hospital, Southern Medical University, Peking University First Hospital, The First People's Hospital of Lianyungang, People's Hospital of Rongcheng, Anhui Medical University
Study start: 20 Mar 2018 (actual)
Primary completion: 30 Mar 2019 (estimated)
Study completion: 30 Jun 2019 (estimated)
First posted: 21 Mar 2018 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Phase I: Screening（V0）

Phase I takes place for about 2-10 days. The purpose is to obtain informed consent and make a preliminary assessment of the patient.

Before carrying out any research procedures, the purpose of the study and study procedures will be explained and the participant's informed consent will be obtained.

Phase Ⅱ: Run-in Period (V1-V2)

Phase Ⅲ: Double-Blind Treatment (V2-V6)

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, investigator)
Number of arms: 8
Model description: Multicenter, randomized, double-blind, controlled clinical trial

Arm	Type	Receives
0 mg folic acid	Sham comparator	Drug: Folic Acid, Drug: EnalaprilEnalapril Maleate (10mg) with 0 mg folic acid
0.4mg Folic acid	Active comparator	Drug: Folic Acid, Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.4mg)
0.6mg Folic acid	Active comparator	Drug: Folic Acid, Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.4mg) with 0.2 mg folic acid
0.8mg Folic acid	Active comparator	Drug: Folic Acid, Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg)
1.2mg Folic acid	Active comparator	Drug: Folic Acid, Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 0.4 mg folic acid
1.6mg Folic acid	Active comparator	Drug: Folic Acid, Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 0.8 mg folic acid
2.0mg Folic acid	Active comparator	Drug: Folic Acid, Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 1.2 mg folic acid
2.4mg Folic acid	Active comparator	Drug: Folic Acid, Drug: Enalapril Maleate and Folic Acid Tablets (Yiye)Enalapril Maleate and Folic Acid Tablets (Yiye) (10mg:0.8mg) with 1.6 mg folic acid

Who may qualify

Ages: 45 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

（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;

Key exclusion criteria (10 listed)

（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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Folic AcidFolic 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.	Drug	0 mg folic acid, 0.4mg Folic acid, 0.6mg Folic acid, 0.8mg Folic acid, 1.2mg Folic acid, 1.6mg Folic acid, 2.0mg Folic acid, 2.4mg Folic acid
Enalapril Maleate and Folic Acid Tablets (Yiye)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.	Drug	0.4mg Folic acid, 0.6mg Folic acid, 0.8mg Folic acid, 1.2mg Folic acid, 1.6mg Folic acid, 2.0mg Folic acid, 2.4mg Folic acid
EnalaprilEnalapril 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.	Drug	0 mg folic acid

Primary outcome

Percentage decrease in blood homocysteine levels by the end of the 8th week from baseline.
Time frame: by the end of the 8th week from the baseline
Hcy percent decrease =（baseline Hcy - end Hcy) /baseline Hcy *100%

3 secondary outcomes

Magnitude of decrease in blood homocysteine by the end of the 8th week from baseline.
Time frame: 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.
Time frame: 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.
Time frame: by the end of the 8th week from the baseline

Results and safety

Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2018.
Background: PubMed 11800055Kjeldsen 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.
Background: PubMed 9569395Collaboration 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.
Background: PubMed 16210710Homocysteine 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.
Background: PubMed 12920077Wilcken 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.
Background: PubMed 18511872Xu 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.
Background: PubMed 22897803Dong 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.
Background: PubMed 29030456Huang 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.
Results publication: PubMed 22230384Qin 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.
Results publication: PubMed 21869730Qin 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.
Results publication: PubMed 22880024Qin 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.
Results publication: PubMed 25771069Huo 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.
Derived from this study: PubMed 38478042Huang 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.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Minqing Tian, PhD contact

86-18818680849

tianminqing@163.com

Xiaoshu Cheng, MD principal investigator

Second Affiliated Hospital of Nanchang University

5 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Folic Acid, Enalapril Maleate and Folic Acid Tablets (Yiye) and Enalapril in people with Hypertension, run by Shenzhen Ausa Pharmed Co.,Ltd at 5 sites in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 18 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Minqing Tian, PhD (86-18818680849, tianminqing@163.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage decrease in blood homocysteine levels by the end of the 8th week from baseline. (time frame: by the end of the 8th week from the baseline). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03472508, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2018.