Clinical trial NCT01848873: Efficacy of Amlodipine-folic Acid Tablets on Reduction of Blood Pressure and Plasma Homocysteine
Official title: Efficacy of Amlodipine-folic Acid Tablets on Reduction of Blood Pressure and Plasma Homocysteine in Patients With Mild to Moderate Hypertension and Hyperhomocysteinemia ：a Double-blind Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Essential Hypertension
Keywords: Hyperhomocysteinemia
Amlodipine-folic acid tablets
Hypertension
MTHFR C677T
Lead sponsor: Shenzhen Ausa Pharmed Co.,Ltd
Sponsor class: INDUSTRY
Collaborators: name: Peking University First Hospital
name: Chinese PLA General Hospital
name: Capital Medical University
name: Fudan University
name: Ruijin Hospital
name: Nanchang University
name: First Affiliated Hospital of Fujian Medical University
name: First Affiliated Hospital of Harbin Medical University
name: China Medical University, China
name: Xi'an Jiaotong University
name: Xuzhou Medical University
name: Anhui Medical University
name: Huazhong University of Science and Technology
name: West China Hospital
name: Guangdong Provincial People's Hospital
name: Second Affiliated Hospital, School of Medicine, Zhejiang University
First posted: 2013-05-08
Enrollment: 756
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the efficacy of Amlodipine-folic Acid Tablets on reduction of blood pressure and plasma homocystein.

Detailed description: Traditional risk factors are estimated to account for only part of cardiovascular disease (CVD) risk. Non-traditional risk factors such as increased homocysteine concentration are believed to be causally related to CVD. The interactive effect between hypertension and hyperhomocysteinemia on the risk of CVD has received great attention. Methylenetetrahydrofolate reductase (MTHFR) was the main regulatory enzymes for homocysteine metabolism. MTHFR converts 5, 10-methylene-THF into 5-methyl-THF. Polymorphism of MTHFR C677T leads to a reduction in enzyme activity, which may lead to an increased concentration of plasma homocysteine and lower levels of serum folate, particularly in those with low folate intake. In the present study, we sought to assess: (1) the efficacy and safety of Amlodipine-folic Acid Tablets in lowering blood pressure and homocystein in patients with mild to moderate hypertension and hyperhomocysteinemia (hcy≥10μmol/L);(2) if the blood pressure and homocysteine-lowering efficacy of Amlodipine-folic Acid Tablets can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms.

In all, about 756 patients with mild or moderate hypertension and hyperhomocysteinemia will be recruited from about 18 hospitals in different Chinese regions. All hospitals are certified as clinical pharmacology centers by the State Food and Drug Administration (SFDA) in China. Eligible subjects are randomly and double-blindly assigned to one of the three treatment groups: 1) amlodipine tablet (5 mg, control group); 2) amlodipine-folic acid tablet (5mg amlodipine combined with 0.4 mg of folic acid, low FA group); or 3) amlodipine-folic acid tablet (5 mg amlodipine combined with 0.8 mg of folic acid, high FA group), once daily for 8 weeks.

The allocation of participants was programmed by an independent statistical coordinating center, encrypted, and sent to each study center. Tablet containers were labeled only with the name of the trial and the allocated concealment number. The participants, care partners, and all staff directly involved in the trial were blinded to interventions during the period of the trial.

Demographic and clinical information were obtained at baseline. Blood pressure was examined at baseline and every two weeks for a total period of 8 weeks. Blood homocysteine and folate concentrations were examined at baseline and at 4 and 8 weeks of the trial. MTHFR C677T genotypes were determined for each study subject.

All analyses will be performed according to the principle of intention to treat.

Eligibility criteria: Inclusion Criteria:

1. Aged 18-75 years;
2. Seated systolic blood pressure (SBP) between 140 mmHg and 180 mmHg and/or seated diastolic blood pressure between 90 mmHg and 110 mmHg;
3. Plasma homocysteine ≥10umol/L；
4. Signed the written informed consent.

Exclusion Criteria:

1. Pregnant women or women within lactation period;
2. Hypersensitive to calcium channel blocker (CCB) or folic acid;
3. Easily hypersensitiveness
4. Diagnosed secondum hypertension or skeptical secondum hypertension;
5. Severe hypertension (sedentary systolic blood pressure≥180mmHg and/or sedentary diastolic blood pressure≥110mmHg)
6. Severe diseases:

   1. Cardiovascular system:
   2. Diagnosed cardia insufficiency (NYHAⅢ level and higher); Hypertrophic obstructive cardiomyopathy (HOCM);Clinical significantly valvular disease of the heart (VDH);Acute coronary syndrome or coronary artery interventional therapy or coronary artery bypass graft within three months; Severe arrhythmia such as atrial flutter, atrial fibrillation, atrioventricular block above Ⅱ level, et al;
   3. Alimentary system:
   4. Active virus hepatitis; Any of alanine aminotransferase (ALT), aspartate aminotransferase (AST), galactosylhydroxylysyl glucosyltransferase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DB) was above 2 times of it's normal value upper limit, albumin (ALB) ≤30g/L;Stomach bulk resect and gastrojejunostomy, stomach intestine malabsorption;
   5. Urinary system:
   6. Serum creatinine≥200μmol/L ; Diagnosed stenosis of renal artery, solitary kidney, renal transplantation;
   7. Endocrine system:
   8. Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus (fasting glucose≥11.1mmol/L); Diagnosed and uncontrolled hyperthyrosis;
   9. Respiratory system:
   10. Pulmonary heart disease , chronic obstructive lung disease;
   11. Nervous or psyche system:
   12. Transient ischemia attach (TIA) or stoke within 3 months; Severe peripheral nerve or vegetative nerve functional disturbance; Psyche or nervous system dysfunction;Drugs or alcohol dependence.
   13. Others:
   14. Malignant tumor, malnutrition, haematogenesis dysfunction, et al;
7. Obvious signs or abnormal laboratory examination;
8. Taking other antihypertensive drugs and unwilling to stop;
9. Taking folic acid or other Vitamin B groups unwilling to stop.

Primary outcomes:
measure: Combined effective rate of blood pressure and plasma homocysteine reduction
timeFrame: Blood pressure was examined at baseline and every 2 weeks for a total period of 8 weeks. Blood homocysteine concentrations were measured at baseline and at 4 and 8 weeks of the trial.
Secondary outcomes:
measure: Blood pressure reduction or plasma homocysteine reduction
timeFrame: Blood pressure was examined at baseline and every two weeks for a total period of 8 weeks. Blood homocysteine concentrations was examined at baseline and at 4 and 8 weeks of the trial.
Other outcomes:
measure: 24-hour ambulatory blood pressure
timeFrame: 24-hour ambulatory blood pressure were examined at baseline and at 8 weeks of the trial in 96 participants.
Locations:
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
state: Anhui
city: Beijing
country: China
facility: Anzhen Hospital,Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Beijing
country: China
facility: Chinese PLA General Hospital
state: Beijing
city: Fuzhou
country: China
facility: First Affiliated Hospital of Fujian Medical University
state: Fujian
city: Guangzhou
country: China
facility: Guangdong General Hospital
state: Guangdong
city: Haibin
country: China
facility: First Affiliated Hospital of Harbin Medical University
state: Heilongjiang
city: Wuhan
country: China
facility: Union Hospital, Tongji Medical College,Huazhong University of Science and Technology
state: Hubei
city: Xuzhou
country: China
facility: The Affiliated Hospital of Xuzhou Medical College
state: Jiangsu
city: Nanchang
country: China
facility: The Second Affiliated Hospital Of Nanchang University
state: Jiangxi
city: Shenyang
country: China
facility: First Affiliated Hospital of China Medical University
state: Liaoning
city: Shanghai
country: China
facility: Ruijin Hospital, Shanghai Jiaotong University School of Medicine
state: Shanghai
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
state: Shanghai
city: Xi'an
country: China
facility: First Affiliated Hospital of the School of Medicine, Xi'an Jiaotong University
state: Shanxi
city: Chengdu
country: China
facility: West China School of Medicine, West China Hospital ,Sichuan University
state: Sichuan
city: Hangzhou
country: China
facility: Second Affiliated Hospital, School of Medicine, Zhejiang University
state: Zhejiang
Study officials:
affiliation: Peking University First Hospital, Beijing, CHINA
name: Yong Huo, MD
role: PRINCIPAL_INVESTIGATOR
References: