Study objectives
The hypothesis of this trial is that fixed dose combination of losartan and amlodipine will be non-inferior to combination of losartan and hydrochlorothiazide in reducing blood pressure in patients with hypertension. Patient blood pressure was measured by conventional and ambulatory monitoring methods, and other vascular hemodynamic parameters were also obtained to test the hypothesis.
Primary endpoint
The primary endpoint is the change in mean sitting systolic blood pressure (msSBP) after 4 weeks of treatment.
Secondary endpoints
Secondary endpoints are changes in msSBP, mean 24-h ambulatory mobile blood pressure (AMBP), mean 24-h ambulatory mobile central SBP (AMcSBP), mean 24-h ambulatory carotid-femoral pulse wave velocity (AMPWV), ambulatory augmentation index (AMAIx), and microalbuminuria/proteinuria after 20 weeks of treatment. Treatment compliance, response rate, and success rate are also included in the secondary efficacy evaluation. Response to treatment is defined as a decrease in systolic blood pressure exceeding 20 mmHg or 10 mmHg for diastolic blood pressure, in accordance with the Korea Food and Drug Administration (KFDA). Treatment success is defined as blood pressure reaching a target of <140/90 mmHg.
Blood pressure measurements
Blood pressure measurements will be obtained in the sitting position with the pressure cuff placed at either the right or left brachial area, using a semi-automated sphygmomanometer (HEM-7080IC, Omron Healthcare Co, Kyoto, Japan). After 5 min of rest, blood pressure will be measured 3 times with an interval of 2 min, and mean pressure will be used for analysis.
Ambulatory monitoring and aortic stiffness measurement
Ambulatory measurements of peripheral and central blood pressure, carotid-femoral pulse wave velocity (cfPWV), and augmentation index (AIx) will be performed using a previously validated, automated oscillometric device (Mobil-O-graph 24 h PWA monitor, IEM Gmbh, Stolberg, Germany) [13,14,15,16].
Study design
The trial has a multicenter, double-blinded, active-controlled, randomized design to compare the efficacy of fixed dose combination of losartan and amlodipine with that of losartan and hydrochlorothiazide. The detailed study design is shown in Fig. 1. Written consent will be obtained for all study patients, and patients will be permitted to request withdrawal from treatment at any time without providing reasons. The primary investigators and the attending physician will also have authority to drop out patients from the trial if it is considered that further participation would be detrimental to the patients’ well-being. After screening, patients eligible for the trial go through an open-labeled run-in period. Patients previously diagnosed with hypertension or those newly diagnosed are given losartan 50 mg daily for 4 weeks. The objective of the run-in period is to uncover patients not responding to a single class of antihypertensive treatment.
After 4 weeks of run-in, only patients with msSBP ≥140 mmHg will go through randomization and be given blinded treatment assignments. For the next 4 weeks, eligible patients are given either losartan/amlodipine 50/5 mg daily or losartan/hydrochlorothiazide 50/12.5 mg daily with a placebo drug of the other group. For patients not responding (msSBP ≥140 mmHg) to the first 4-week arm of the trial, doses will be increased to losartan/amlodipine 100/5 mg daily or losartan/hydrochlorothiazide 100/25 mg daily. The second arm of the trial will last for 16 more weeks. Patients responding to the initial dose will be maintained on their regimen.
Randomization is achieved by block randomization method to avoid bias and increase inter-group comparability. Block size is determined by an independent individual not participating in the trial. Patients are randomized 1:1 to either losartan/amlodipine or losartan/hydrochlorothiazide. Randomization results are kept in a sealed envelope and opened only in case of serious adverse events. Both the investigators and study participants are blinded to treatment group. To avoid treatments being visually distinguishable, the study drug and placebo are identical in appearance.
Patient population
Inclusion criteria
Patients are to be recruited from 20 nationwide medical centers in Korea. Men and women from ages 19 to 80, with history of hypertension or those newly diagnosed with a systolic BP ≥140 mmHg are to be included in the study.
Exclusion criteria
The exclusion criteria are: (1) mean sitting diastolic blood pressure (msDBP) ≥110mgHg or msSBP ≥180 mmHg at screening or randomization; (2) variability of ≥20 mmHg in SBP or ≥10 mmHg in DBP between three measurements, or differences of ≥20/10 mmHg in left-to-right brachial values of SBP or DBP; (3) secondary hypertension; (4) malignant hypertension; (5) allergies or contraindications to ARB, CCB, or sulfonamides; (6) uncontrolled diabetes mellitus (HbA1c ≥10%); (7) history of New York Heart Association (NYHA) class III to IV heart failure, angina, myocardial infarction, cardiomyopathy, arrhythmia, or aortic stenosis requiring treatment within 6 months; (8) cerebral vascular disease within 6 months; (9) serious liver or renal dysfunction; (10) symptomatic hyperuricemia or gout; (11) galactose or lactose-intolerance; (12) patients with diabetes or moderate to severe renal dysfunction on drugs containing aliskiren; (13) pregnancy or the possibility of pregnancy, or breast feeding; (14) unable to withhold current medication; (15) prescription of other study drugs within 4 weeks; and (18) abnormal laboratory results (AST, ALT >3ULN, Cr >2.0 mg/dL, K+ <3.5 or >5.5 mEq/L, Na + <125 mEq/L, Protein >2+ on dipstick, or protein/creatinine >1000 mg/g on spot urine).
Statistical analysis
Sample size
Sample size is calculated with 90% power to detect a difference in change of SBP of 3 mmHg between two groups at a two-sided significance level of 5%. To satisfy these assumptions and allowing for a drop-out rate of 20%, a total of 238 patients (119 for each treatment arm) are required for the trial.
Efficacy evaluation
Baseline characteristics will be compared using the Students t-test for continuous variables and the chi-square or Fisher’s exact test for categorical variables. Primary endpoint evaluation will be carried out using the two-sample t-test or Mann-Whitney test for inter-group comparison. For secondary endpoints, two-sample t-test and Wilcoxon’s rank sum test will be used for continuous variables, and the chi-square or Fisher’s exact test for categorical variables. Comparison of groups in achieving blood pressure target will be carried out using chi-square or McNemar’s test. All efficacy evaluations will be performed on the full analysis set (FAS). The FAS is a modified intention-to-treat set that includes patients receiving at least one dose of the study drug and having undergone at least one efficacy evaluation. Additional analysis will also be performed on the per protocol set. In order to minimize missing data, outcome data for patients who were discontinued from the study due to various reasons will be obtained and used for analysis. All investigators, sponsors, and regulators will aim to maximize the number of participants who are maintained on the assigned treatment until outcome data are collected.
Safety analysis
Safety analysis will be performed on all patients who has received the study drug at least once. Patients with self-reported or observed adverse symptoms will be seen by the attending physician and recorded according to treatment group and severity, and encoded to a system-organ class according to the Medical Dictionary for Regulatory Activities (MedDRA), version 16.0. The association with symptoms and drug treatment will also be evaluated. Abnormalities in laboratory results will be followed up until normalization and recorded for safety analysis.
