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.
Full Title of Study: “Manidipine Versus Amlodipine in Patients With Hypertension: Effects on Peripheral Edema Evaluated by Bioimpedance Analysis”
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Treatment
- Masking: Single (Participant)
- Study Primary Completion Date: May 15, 2018
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.
- Drug: Manidipine 20mg
- 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.
- Drug: Amlodipine 10mg
- 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.
Arms, Groups and Cohorts
- Experimental: Manidipine 20mg
- 50 patients will be administered orally manidipine 20mg/day after 1~2 week run-in period
- Active Comparator: Amlodipine 10mg
- 50 patients will be administered orally amlodipine 10mg/day after 1~2 week run-in period
Clinical Trial Outcome Measures
- Change in leg edema score (Extracellular Water(ECW) to Total Body Water(TBW))
- Time Frame: Up to 8 weeks
- Changes in segmental (each arm/leg, trunk) edema score
- Time Frame: Up to 8 weeks
- Changes in Blood Pressure (BP)
- Time Frame: Up to 8 weeks
- Incidences of AEs
- Time Frame: Up to 8 weeks
Participating in This Clinical Trial
- 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).
Gender Eligibility: All
Minimum Age: 20 Years
Maximum Age: 80 Years
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Korea University Guro Hospital
- Takeda Pharmaceuticals International, Inc.
- Provider of Information About this Clinical Study
- Principal Investigator: Eung Ju Kim, Professor – Korea University Guro Hospital
- Overall Official(s)
- Eung Ju Kim, MD, Principal Investigator, Professor
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