China Stroke Primary Prevention Trial

Primary Hypertension Clinical Trial

— CSPPT  

Official title:

Enalapril Maleate and Folic Acid Tablets for Primary Prevention of Stroke in Patients With Hypertension: a Post-marketing, Double-blind, Randomized Controlled Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00794885
• Other study ID #: Ausa-CSPPT
• Status: Completed
• Phase: Phase 4
• First received: November 19, 2008
• Last updated: August 11, 2014
• Start date: May 2008
• Est. completion date: June 2014

Study information

• Verified date: August 2014
• Source: Shenzhen Ausa Pharmed Co.,Ltd
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this trial is to confirm that enalapril maleate and folic acid tablets is more effective in preventing stroke among the patients with primary hypertension when compared to enalapril maleate.

Description:

Primary hypertension is the most important risk factor leading to cardiovascular events. Successful management of hypertension is a key to prevent these events. Hyperhomocysteinemia (HHcy) is another independent risk factor, especially for stroke. Our team's prospective nested case-control study of 39165 subjects in China showed that incidence of cardiovascular events (especially stroke) was strongly associated with plasma level of total homocysteine (tHcy). The coexistence of hypertension and HHcy dramatically increased the risk of stroke by 25 to 30 times as compared to the subjects without the two risk factors (Graham et al, 1997). Findings from previous and our studies clearly indicate that simultaneous control of hypertension and HHcy is pivotal in reducing cardiovascular events morbidity and mortality in China.

It has been well documented that folic acid is effective in lowering the level of plasma tHcy. While controversial remains on its efficacy on preventing cardiovascular events, a study done by our team: "Efficacy of folic acid supplementation in stroke prevention: a meta-analysis" (Wang et al, 2007) provide coherent evidence that folic acid supplementation can decrease the risk of stroke by 18%, and 25% in populations where folic fortification was not issued, or used for primary prevention.

C677T gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) is one of the genetic determinators of plasma tHcy level. Observational studies showed that individuals with TT genotype tend to have high plasma tHcy and elevated risk of cardiovascular events (Cronin et al. 2005), and folic acid supplementation led to a remarkable reduction in plasma tHcy. In short, previous studies by others and by our team have provided strong rationale for our proposed trial as detailed below.

The hypothesis of the current study is that a combination of antihypertensive drug (e.g., enalapril) with folic acid is not only efficacious, but also is safe and highly cost-effective than antihypertensive (e.g., enalapril) used alone to prevent stroke in hypertensive patients.

This trial will enroll 20,000 patients with primary hypertension and with known MTHFR C677T genotype. Subjects will be first stratified by genotypes, and then randomly assigned to treatment groups. The study patients will be instructed to take orally enalapril 10 mg daily or enalapril/folic acid 10mg/0.8mg tablets daily for a maximum of 5 years. The follow-up is given every 3 months.

The incidence and time of first-time stroke episode (primary endpoint) or composite cardiovascular events are used as endpoints. They will be compared by treatment groups with and without stratification by C677T gene polymorphisms. The potential interaction between treatment groups and C677T gene polymorphisms on therapeutic efficacy will also be tested.

This will be the first and largest trial of this kind in Chinese population. The findings from this trial may have the potential to transform current clinical and public health findings into practice.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20702
• Est. completion date: June 2014
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 45 Years to 75 Years

Eligibility

Inclusion Criteria:

• BP=140/90 mmHg in both of the two screening visits or currently under anti-hypertension treatment

• 45 - 75 years old

• Successful determination of MTHFR C677T genotype

• For pre-menopausal women, agreed to use contraceptives during the trial

• Signed the written informed consent

Exclusion Criteria:

• Having a history of stroke

• Having a history of myocardial infarction

• Having a history of physician diagnosed heart failure

• Post- coronary revascularization

• Severe somatic disease such as cancer

• Secondary hypertension

• Congenital or acquired organic heart diseases

• Contraindicated to angiotensin-converting enzyme inhibitor(ACEI)

• History of ACEI adverse effects

• Currently long-term use of folic acid or vitamin B12 or vitamin B6

• Pregnant or child breastfeeding women

• Severe mental disorders

• Lab tests indicating abnormal liver or kidney function

• Unwilling to participate the trial, unwilling to change the current antihypertensive treatment

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Hypertension
• Primary Hypertension

Intervention

Drug:
• Enalapril/folic acid
Enalapril/folic acid, (10mg enalapril/0.8mg folic acid)/tablet, taken orally and once daily for a maximum of 5 years. Combination with other anti-hypertension drugs are allowed.
• Enalapril maleate
Enalapril, 10mg/tablet, taken orally once daily for a maximum of 5 consecutive years. Combination with other anti-hypertension drugs are allowed.

Locations

Country	Name	City	State
China	Anqing Branch, Anhui Institute of Biomedical Research	Anqing City	Anhui
China	Lianyungang Center for Advanced Research in Cardiovascular Diseases	Lianyungang	Jiangsu

Sponsors (2)

Lead Sponsor	Collaborator
Shenzhen Ausa Pharmed Co.,Ltd	Anhui Medical University

Country where clinical trial is conducted

China, 

References & Publications (3)

Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke. 2005 Jul;36(7):1581-7. Epub 2005 Jun 9. — View Citation

Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Lúis AC, Parrot-Rouland FM, Tan KS, Higgins I, Garcon D, Andria G, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997 Jun 11;277(22):1775-81. — View Citation

Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007 Jun 2;369(9576):1876-82. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Malignant tumors		during the trial period	Yes
Primary	First attack of symptomatic stroke ( ischemic or hemorrhagic)	Patients are followed-up every 3 months. All endpoint outcomes are assessed by the Endpoint Adjudication Committee of the study.	during the trial period	No
Secondary	Composite major cardiovascular events		during the trial period	No
Secondary	All-cause death		during the trial period	Yes
Secondary	First attack of ischemic stroke and resultant death		during the trial period	No
Secondary	First attack of hemorrhagic stroke and resultant death		during the trial period	No
Secondary	Myocardial infarction and resultant death		during the trial period	No