Manidipine Versus Amlodipine in Patients With Hypertension

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the effect of a third-generation Calcium Channel Blocker (CCB), manidipine, compared with second-generation Calcium Channel Blocker (CCB), amlodipine, on the development of peripheral edema using Direct Segmental Multi-Frequency Bioelectrical Impedance Analysis (DSM-BIA) method in patients with mild to moderate essential hypertension. Investigator expects this study could show more objective evidence of better safety of manidipine compared with amlodipine for peripheral edema.

Detailed Description
-----------------
Dihydropyridine Calcium Channel Blockers (CCBs) are one of the most commonly used potent antihypertensive agents. Their vasodilatory effects are associated with Adverse Effects (AEs) such as peripheral edema, headache and flushing. The incidence of peripheral edema with Calcium Channel Blocker (CCB) is 6% in a recent systematic review and is clearly dose-dependent and more common in women, in obese and in elderly hypertensives. Peripheral edema could be a cause for poor persistence with therapy or antihypertensive treatment withdrawal and has a deleterious impact on health-related quality of life. A recent meta-analysis of head-to-head trials to compare the efficacy and safety profile of manidipine and amlodipine showed significantly better safety of manidipine: the Relative Risk (RR) for adverse event was 0.69 (0.56-0.85), and particularly for ankle edema Relative Risk (RR) was 0.35 (0.22-0.54). Although peripheral edema is an important issue in Calcium Channel Blocker (CCB) treatment, techniques (e.g, ankle-foot volume using a water displacement measurement, plethysmography, and pretibial subcutaneous tissue pressure) for the objective measurement are not generally available in a clinical setting. Most clinical studies relied on self-report of peripheral edema that is not a reliable objective method. Recently, Bioelectrical Impedance Analysis (BIA) has become increasingly popular for estimating body composition, including Extracellular Water (ECW) and Intracellular Water (ICW), fat mass and fat-free mass. Mechanistically, the Calcium Channel Blocker (CCB)-related peripheral edema is likely due to distal arteriolar dilatation with capillary leak to tissue spaces. Because BIA method can measure the edema as the ratio of Extracellular Water (ECW) to Total Body Water (TBW), it may reflect the Calcium Channel Blocker (CCB)-related edema. Moreover, the Direct Segmental Multi-frequency Bioelectrical Impedance Analysis (DSM-BIA) has been validated to assess segmental body (i.e., trunk, arms and legs) composition in addition to total body composition and can provide segmental edema score as well as total edema score. This new, previously not reported method is expected to provide more objective and precise data for peripheral edema.

Official Title
-----------------
Manidipine Versus Amlodipine in Patients With Hypertension: Effects on Peripheral Edema Evaluated by Bioimpedance Analysis

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: Manidipine 20mg
* Drug: Amlodipine 10mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female outpatients between the ages of 20 and 80 years with uncomplicated essential hypertension are eligible. Inclusion criteria requires that patients have either stage I or stage II hypertension (mean sitting systolic Blood Pressure (BP) 140-179 mmHg, diastolic BP 90-109 mmHg). The patients are newly diagnosed or known hypertensive subjects who were not taking antihypertensive agents for more than the last 4 weeks. Exclusion Criteria: Patients are excluded from the study if they have any evidence of clinically significant concurrent medical conditions including cardiac, renal, hepatic, gastrointestinal, or endocrinologic disease. Patients are also excluded if they have known hypersensitivity or serious drug reactions to Calcium Channel Blockers (CCBs), any evidence of prior deep vein thrombosis, lymphatic disease, or concurrent requirement for medications that could affect Blood Pressure (BP) or salt and water retention (e.g, nonsteroidal antinflammatory drugs, estrogen containing drugs).

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Manidipine 20mg/day, Amlodipine 10mg/day Sealed envelope method randomization according to gender and age 25 males under 55 years old 25 males more than 55 years old 25 females under 55 years old 25 females more than 55 years old
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Manidipine 20mg<br>50 patients will be administered orally manidipine 20mg/day after 1 2 week run-in period | Drug: Manidipine 20mg<br>* After a 1 2-week run-in period, patents will be randomized to receive manidipine (20 mg/day; n=50) for a 8-week open-labeled phase. Study drugs will be administered orally and once daily between 8:00am and 10:00am. BP, heart rate, adverse events and concomitant therapy are assessed and a physical examination is performed at each visit. A 12-lead standard ECG is obtained and hematology, clinical biochemistry and urine analysis investigations performed at the screening visit. A Bioelectrical Impedance Analysis (BIA) is undertaken at the screening visit and at the end of the 8-week treatment course. Patients have to attend the clinic visit every 4 weeks during the treatment period.<br>* Other names: Madipine Tab(Manidipine Hydrochloride) 20mg (CJ);|
| Active Comparator: Amlodipine 10mg<br>50 patients will be administered orally amlodipine 10mg/day after 1 2 week run-in period | Drug: Amlodipine 10mg<br>* After a 1 2-week run-in period, patents will be randomized to receive amlodipine (10 mg/day; n=50) for a 8-week open-labeled phase. Study drugs will be administered orally and once daily between 8:00am and 10:00am. BP, heart rate, adverse events and concomitant therapy are assessed and a physical examination is performed at each visit. A 12-lead standard ECG is obtained and hematology, clinical biochemistry and urine analysis investigations performed at the screening visit. A Bioelectrical Impedance Analysis (BIA) is undertaken at the screening visit and at the end of the 8-week treatment course. Patients have to attend the clinic visit every 4 weeks during the treatment period.<br>* Other names: Amlodipine Pfizer 10mg (Pfizer);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in leg edema score (Extracellular Water(ECW) to Total Body Water(TBW)) |  | Up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in segmental (each arm/leg, trunk) edema score |  | Up to 8 weeks | 
| Changes in Blood Pressure (BP) |  | Up to 8 weeks | 
| Incidences of AEs |  | Up to 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Peripheral Edema, Bioimpedance Analysis