FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC): study protocol for randomized controlled trial

Kim et al. Trials (2017) 18:632 DOI 10.1186/s13063-017-2375-8 STUDY PROTOCOL Open Access FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC): study protocol for randomized controlled trial Jang-Young Kim1†, Jung-Woo Son1†, Sungha Park2, Tea-Hyun Yoo3, Yong-Jin Kim4, Dong-Ryeol Ryu5* and Ho Jun Chin6 Abstract Background: Fimasartan is the ninth angiotensin receptor blocker to be developed. However, it has not yet been evaluated for reno-protective effects in hypertensive diabetic chronic kidney disease (CKD). The target blood pressure (BP) for hypertensive diabetic CKD is also a controversial topic. This trial was designed to assess the reno-protective effects of fimasartan compared to those of losartan as a primary outcome. This study also compares the two drugs with regard to cardiovascular and renal outcomes in accordance with target systolic BP (SBP) (as secondary outcomes). Methods: This study is a prospective, phase III, randomized, double-blind, active-controlled, non-inferiority, four-parallel group, dose-titration, multicenter trial. We recruit patients with hypertensive diabetic CKD with overt proteinuria. Participants will be randomized into four groups (1:1:1:1): fimasartan standard SBP control (SBP < 140 mmHg); fimasartan strict SBP control (SBP < 130 mmHg); losartan standard SBP control; and losartan strict SBP control. After 24 weeks, all individuals are treated with fimasartan for an additional 120 weeks in an open-label design, maintaining their assigned SBP control groups as randomized. The primary endpoint is the rate of change in proteinuria, which is assessed using the spot urine albumin– creatinine ratio at 24 weeks. The secondary endpoints are the cardiovascular and renal outcomes at 144 weeks compared between the strict SBP and standard SBP control groups. Discussion: The FANTASTIC is a clinical study to provide: (1) the reno-protective effect of fimasartan; and (2) the target BP to reduce adverse outcomes in hypertensive diabetic CKD with overt proteinuria. Trial registration: Clinicaltrials.gov, NCT02620306. Registered on 1 December 2015. Keywords: Proteinuria, Chronic kidney disease, Hypertension, Diabetes mellitus * Correspondence: † Equal contributors 5 Department of Internal Medicine, School of Medicine, Ewha Womans University, 1071, Anyangcheon-ro, Yangcheon-gu, Seoul 158-710, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. Trials (2017) 18:632 Background Hypertension affects approximately 40% of adults worldwide [1] and about two-thirds of patients with diabetes have concomitant hypertension [2]. Both hypertension and diabetes have a variety of vascular complications, including macrovascular and microvascular effects. The macrovascular complications of hypertension and diabetes include coronary artery disease, stroke, and peripheral vascular disease. The microvascular complications include retinopathy, nephropathy, and neuropathy. Hypertension and diabetes also increase the risk of developing newonset chronic kidney disease (CKD) [3]. The progression of CKD is accompanied by microvascular complications. CKD increases a patient’s risk of stroke, coronary artery disease, and all-cause mortality. The annual mortality rate of those patients who progress to require dialysis is about 10–20% [4, 5]. Given the association between CKD and cardiovascular disease, it is important to suppress CKD progression in patients with both hypertension and diabetes. The degree of baseline proteinuria is correlated to the future progression of CKD [6–8]. High albuminuria was shown to be associated with increased risk of myocardial infarction, stroke, first hospitalization for heart failure, unstable angina, coronary or peripheral revascularization, and cardiovascular death [9]. Recent evidence has shown that reducing proteinuria can prevent the progression of CKD. Angiotensin II receptor blockers (ARB) have also been shown to reduce CKD progression of CKD [10–14]. Most hypertension guidelines recommend that angiotensin converting enzyme inhibitors (ACEI) or ARBs be used in patients with hypertensive diabetes [15–17]. There are few studies that directly compare the renal efficacy of two ARBs in hypertensive diabetes. In one comparison study of hypertensive type 2 diabetic patients with overt nephropathy, telmisartan were found to have similar renal efficacy to valsartan [18]. In another comparison study, telmisartan was found to be superior to losartan at reducing the geometric mean urinary protein–creatinine ratio without a change in blood pressure (BP), dietary sodium, or estimated glomerular filtration rate (eGFR) [19]. Therefore, although ARBs have a renoprotective class effect, there are relative differences in each drug’s efficacy. Fimasartan was the ninth ARB approved for the treatment of hypertension by the Korean Ministry of Food and Drug Safety in 2010; it entered the market in 2011 [20]. Its chemical characteristics are as follows: 2-n-butyl-5dimethylaminothiocarbonyl methyl-6-methyl-3-([2’-(1Htetrazol-5-yl) biphenyl-4-yl] methyl) pyrimidin-4(3H)one); molecular formula, C27H31N7OS; molecular weight, 501.65; formally known as BR-A-657. Despite the proven antihypertensive effect, however, the renal efficacy and safety of fimasartan in hypertensive diabetic CKD have not been studied or compared to those of other Page 2 of 9 ARBs. Therefore, this randomized multicenter clinical trial compares the renal efficacy and safety of fimasartan to those of losartan, which has already been shown to have a renal protective effect [12]. The target BP in diabetic CKD remains controversial. There are inconsistencies in the current guidelines regarding target BP for patients with diabetic CKD from KDIGO (Kidney Disease Improving Global Outcomes), ESC (European Society of Cardiology), and JNC (Joint National Committee) 8 [15, 16, 21]. The current KDIGO guideline recommends that the target goal is a systolic BP (SBP) < 130 mmHg and diastolic BP (DBP) < 80 mmHg in diabetic CKD, with a urine albumin excretion > 30 mg/day. [21] The JNC 8 panel recommends that hypertensive adults with diabetic or non-diabetic CKD keep their BP < 140/ 90 mmHg. [15] Thus, the purpose of the present study, FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with los (...truncated)