China Stroke Primary Prevention Trial (CSPPT)
Drug: Enalapril/folic acid
Drug: Enalapril maleate
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|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.|
- First attack of symptomatic stroke ( ischemic or hemorrhagic) [ Time Frame: during the trial period ] [ Designated as safety issue: No ]Patients are followed-up every 3 months. All endpoint outcomes are assessed by the Endpoint Adjudication Committee of the study.
- Composite major cardiovascular events [ Time Frame: during the trial period ] [ Designated as safety issue: No ]
- All-cause death [ Time Frame: during the trial period ] [ Designated as safety issue: Yes ]
- First attack of ischemic stroke and resultant death [ Time Frame: during the trial period ] [ Designated as safety issue: No ]
- First attack of hemorrhagic stroke and resultant death [ Time Frame: during the trial period ] [ Designated as safety issue: No ]
- Myocardial infarction and resultant death [ Time Frame: during the trial period ] [ Designated as safety issue: No ]
- Malignant tumors [ Time Frame: during the trial period ] [ Designated as safety issue: Yes ]
|Study Start Date:||May 2008|
|Study Completion Date:||June 2014|
|Primary Completion Date:||August 2013 (Final data collection date for primary outcome measure)|
Experimental: Enalapril/folic acid
A fixed combination drug is given. The dose is fixed in enalapril 10 mg / folic acid 0.8 mg per day.
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.
Other Name: Enalapril Maleate and Folic Acid Tablet
Active Comparator: Enalapril
Enalapril maleate 10 mg per day is given
Drug: Enalapril maleate
Enalapril, 10mg/tablet, taken orally once daily for a maximum of 5 consecutive years. Combination with other anti-hypertension drugs are allowed.
Other Name: Lameiya,Yabao Pharmaceutical
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00794885
|Anqing Branch, Anhui Institute of Biomedical Research|
|Anqing City, Anhui, China, 246000|
|Lianyungang Center for Advanced Research in Cardiovascular Diseases|
|Lianyungang, Jiangsu, China, 222003|
|Principal Investigator:||Yong Huo, M.D.||The First Hospital, Beijing University|