Efficacy and Tolerability of Once-Daily Oral Fimasartan 20 to 240 mg/d in Korean Patients with Hypertension: Findings from Two Phase II, Randomized, Double-Blind, Placebo-Controlled

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Clinical Therapeutics/Volume 34, Number 6, 2012

Efficacy and Tolerability of Once-Daily Oral Fimasartan20 to 240 mg/d in Korean Patients with Hypertension:Findings from Two Phase II, Randomized, Double-Blind,Placebo-Controlled Studies

Howard Lee, MD, PhD1; Han-Mo Yang, MD2; Hae-Young Lee, MD2;ae-Joong Kim, MD, PhD3; Dong-Ju Choi, MD, PhD4; Ki-Bae Seung, MD, PhD5;un-Seok Jeon, MD, PhD6; Jong-Won Ha, MD, PhD7; Se-Joong Rim, MD, PhD8;

eong Bae Park, MD, PhD9; Joon-Han Shin, MD10; and Byung-Hee Oh, MD2

1Center for Drug Development Science, Department of Bioengineering and Therapeutic Sciences, School ofharmacy, University of California, San Francisco, California, and University of California Washingtonenter, Washington, DC; 2Department of Internal Medicine, Seoul National University College of

Medicine, Seoul National University Hospital, Seoul, Korea; 3Department of Cardiology, Asan Medicalenter, University of Ulsan, College of Medicine, Seoul, Korea; 4Department of Internal Medicine, Seoulational University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea;

5College of Medicine, The Catholic University of Korea, Cardiovascular Center, Seoul St. Mary’s Hospital,eoul, Korea; 6Division of Cardiology, Sungkyunkwan University School of Medicine, Samsung Medical

Center, Seoul, Korea; 7Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College ofMedicine, Seoul, Korea; 8Cardiology Division, Gangnam Severance Hospital, Yonsei University College ofMedicine, Seoul, Korea; 9Division of Cardiology, Cheil General Hospital, Kwandong University College ofMedicine, Seoul, Korea; and 10Department of Cardiology, Ajou University School of Medicine, Ajou

niversity Hospital, Suwon, Korea

ABSTRACTBackground: Fimasartan is a selective angiotensin II

receptor blocker developed for once-daily dosing.Objectives: To meet the regulatory requirements for

approval of an antihypertensive treatment in Korea,this pair of studies was conducted to evaluate the effi-cacy and tolerability of fimasartan, to determine itsdose-response relationship and minimum effectivedose, and to characterize its blood pressure (BP)-reduc-tion profile over the dosing interval.

Methods: These 2 Phase II, randomized, double-blind, placebo-controlled, parallel-group, and dose-re-sponse studies enrolled male or nonchildbearing fe-male Korean patients aged 18 to 65 years (study 1) or18 to 70 years (study 2) with essential hypertension(sitting diastolic BP [DBP] 95–�115 mm Hg [study 1]or 90–�110 mm Hg [study 2]). Patients were ran-domly assigned to receive fimasartan 20, 60, 120, or180 mg (study 1) or 20, 60, 120, or 240 mg (study 2) or
placebo in the same ratio, once daily for 4 weeks
June 2012

(study 1) or 8 weeks (study 2). Clinic BP was measuredat trough, and change from baseline in DBP at week 4(study 1) or 8 (study 2) was the primary efficacy endpoint. In study 1, 24-hour ambulatory BP monitoring(ABPM) was conducted. Treatment-emergent adverseevents (TEAEs) were assessed using a structured ques-tionnaire, laboratory testing, physical examination,and ECG readings.

Results: Totals of 61 and 195 patients participatedin studies 1 and 2, respectively (68% male; mean age,50.1 and 55.1 years; DBP, 98.7 and 103.6 mm Hg;systolic BP, 147.0 and 158.1 mm Hg), of whom 52(85.2%) and 169 (86.7%) completed each study. Datafrom ABPM were obtained from 45 patients (73.8%),and safety profile was evaluated in 225 participants.

Accepted for publication April 20, 2012.http://dx.doi.org/10.1016/j.clinthera.2012.04.0210149-2918/$ - see front matter

© 2012 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics

Four-week treatment with fimasartan 180 mg oncedaily was associated with a significantly greater meanreduction in DBP compared with placebo in study 1(�16.4 vs �5.5 mm Hg; P � 0.022). In study 2, fi-

asartan 60, 120, and 240 mg once daily were associ-ted with significantly greater reductions in DBP afterweeks of treatment compared with placebo (�14.4,14.1, and �12.7 vs �5.8 mm Hg, respectively; P �.0001–� 0.005). Fimasartan 60 mg once daily washe minimum effective dose, and the dose-response re-ationship was flat at doses �60 mg once daily. BPeduction was maintained over the full 24-hour dosingnterval (trough-to-peak ratios: 0.41–0.98). The pro-ortions of patients who experienced TEAEs wereomparable among the treatment groups in both stud-es, with headache (9.8%) and dizziness (4.4%) beingost commonly reported. No serious AEs were

eported.Conclusions: Once-daily oral administration of fi-

asartan was well tolerated and efficacious in reduc-ng BP in these hypertensive Korean patient popula-ions. ClinicalTrials.gov identifiers: NCT00937651nd NCT00923611. (Clin Ther. 2012;34:1273–1289)

2012 Elsevier HS Journals, Inc. All rights reserved.Key words: 24-hour ambulatory blood pressure

onitoring, angiotensin II receptor blocker, efficacy,ssential hypertension, fimasartan, tolerability.

INTRODUCTIONFimasartan, an angiotensin II receptor blocker (ARB)with a selective type 1 (AT1) receptor blockade effect,1

has been developed for once-daily dosing to treat pa-tients with hypertension.2 Two Phase I studies con-ducted in healthy, mostly white volunteers reportedthat repeated oral administration of fimasartan up to360 mg once daily had a safety profile comparable tothat of placebo, with dizziness being the most com-monly reported adverse event (AE).3 The pharmacoki-etic properties of fimasartan were also favorable, that

s, rapid absorption, dose-linearity, negligible metabo-ism (most excreted unchanged in bile), minimal accu-ulation (�30% when dosed once daily), unremark-

ble food effect (AUC lowered by 5% in the fed state),nd a relatively long half-life of 14.0 to 17.9 hours.3

The pharmacodynamic results from those Phase Istudies suggested that fimasartan may have potential asan effective antihypertensive treatment. For example,
fimasartan was associated with significantly increased
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levels of plasma renin activity, angiotensin I, and ang-iotensin II for up to 48 hours postdose, while aldoste-rone and angiotensin-converting enzyme activity werenot affected.3 These pharmacodynamic effects, partic-larly the increase in plasma angiotensin II level, arettributed to fimasartan through its blocking of theT1 receptor. These effects have been noted with other

ARBs, such as losartan4 and valsartan,5 and are theechanism of action for blood pressure (BP) reductiony these and other ARBs.6–8 Additionally, fimasartanse was associated with reductions in supine andtanding BP for up to 24 hours after administration inany healthy subjects.3 Therefore, it is reasonable to

suppose that fimasartan may decrease BP in hyperten-sive subjects by antagonizing angiotensin II receptors,and once-daily oral administration seems appropriateto achieve this intended beneficial effect.

These results in the safety profile, pharmacokinetics,and pharmacodynamics of fimasartan have led to thefollowing questions: (1) Does fimasartan significantlydecrease BP in hypertensive patients, and is this de-crease significantly greater than with placebo?; (2)What is the dose-response relationship and the mini-mum effective dose of fimasartan?; (3) Is once-dailyadministration of fimasartan able to maintain BP re-duction throughout, especially toward the end of thedosing interval?; and (4) Is fimasartan treatment welltolerated? To answer these questions, 2 studies wereconducted in Korean patients with essential hyperten-sion to explore the efficacy and tolerability of fimasar-tan at various oral doses. Based on the results fromthese studies, the dose-response relationship of fi-masartan was assessed, and the optimal doses for fur-ther clinical studies of fimasartan were determined.Moreover, 24-hour ambulatory blood pressure moni-toring (ABPM) was used in 1 of the studies for charac-terization of the BP-lowering profile of fimasartan overthe dosing interval. The main results of these studiesare reported in this article.

PATIENTS AND METHODSInclusion Criteria

This pair of Phase II studies enrolled male or non-childbearing female patients aged 18 to 65 years(18–70 years in study 2) with essential hypertension(sitting diastolic BP [DBP], 95–�115 mm Hg in study1, 90–�110 mm Hg in study 2, after washout of anti-hypertensives of �1 week and a 2-week placebo run-
in, with a difference from before to after run-in of �7
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mm Hg) who consented to participate. The emphasison DBP as the sole clinical eligibility criterion wasbased on the Clinical Trial Guidance for Antihyperten-sive Agents9 by the Korean Food and Drug Adminis-ration, as these studies were conducted as a part of theegulatory requirements in Korea to approve fimasar-an for use in patients with hypertension. Therefore,atients with isolated systolic hypertension werexcluded.

Patients were excluded if they had sitting systolic BPSBP) �200 mm Hg; secondary hypertension; ortho-tatic hypotension (ie, decrease �20 in standing SBPnd/or �10 mm Hg in standing DBP from the corre-ponding supine BP after a rest of �5 minutes in theupine position); systemic disease that may have af-ected the absorption, distribution, metabolism, or ex-retion of fimasartan; a history of myocardial infarc-ion or coronary arterial disease; clinically significantongestive heart failure or cardiac valve defect identi-ed within the 6 months before screening; insulin-de-endent diabetes or uncontrolled diabetes (ie, hemo-lobin [Hb] A1c �9%, increased dose of an oral

hypoglycemic agent within the 12 weeks before screen-ing, and/or active insulin treatment at screening); con-current drug treatment that may have affected BP; se-rum creatinine �1.5-fold the upper limit of normal(ULN); aspartate aminotransferase (AST) or alanineaminotransferase (ALT) �2-fold ULN; and/or anyother clinically significant abnormality on laboratorytesting. Patients weighing �85% or �135% of theideal body weight based on the Modified MetropolitanLife Insurance table,10 with a known allergy or contra-ndication to ARBs, and/or a history of alcohol or sub-tance abuse were also excluded.

Study Design, Setting, and ProceduresStudies 1 and 2 used a randomized, double-blind,

placebo-controlled, parallel-group, and dose-responsedesign. The major differences between the 2 studieswere treatment duration (4 and 8 weeks in studies 1and 2, respectively) and fimasartan doses (20, 60, and180 mg once daily in study 1; 20, 60, 120, and 240 mgonce daily in study 2). Study 1 took place at the car-diovascular clinic of Seoul National University Hospi-tal in Seoul, Korea, whereas 9 university or tertiary-care hospitals in Seoul and its suburban areas,including Seoul National University Hospital, partici-pated in the longer-term, multicenter study 2. All of the
study protocols were reviewed and approved by the
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institutional review board at each participating hospi-tal prior to any patient enrollment. In addition, thestudies were conducted in accordance with the currentGood Clinical Practices11 and other applicable lawsnd regulatory requirements in Korea.12

Eligible patients were randomly assigned to receive1 of the fimasartan doses or placebo in the same ratio.To this end, a randomization sequence was generatedusing the PROC PLAN procedure in SAS (version9.1.3, SAS Institute Inc, Cary, North Carolina) with ablock size of 4 (study 1) and 5 (study 2), respectively.Randomization was also stratified by hospital in study2. Based on the randomization sequence, the prepack-aged study drugs were provided by the sponsor in aconcealed container, and the clinical pharmacist ineach participating hospital directly distributed them tothe participants. The investigators, study personnel,and participants were masked to treatment assignmentthroughout the study. Blinding was further ensured bythe identical shape, weight, and external appearance ofall of the study drugs and packaging.

Patients were instructed to orally take the assigneddrug once daily at the same time each day, after themorning meal, with the exception of days on whichstudy procedures were scheduled (weeks 0 [baseline],1, 2, 3, and 4 in study 1; weeks 0, 2, 4, and 8 in study2). During these study visits, assessments of treatment-emergent AEs (TEAEs) using a structured question-naire, BP measurements, physical examination, clinicallaboratory testing (hematology, blood chemistry, uri-nalysis), and 12-lead ECG (screening and last visitsonly; MAC 5000 ECG system, GE Healthcare, Mu-nich, Germany) were performed. All of the clinical lab-oratories in the participating hospitals were accreditedby the Korean Society for Laboratory Medicine andhad participated in the annual quality-assurance pro-gram sponsored by the Korean Association of QualityAssurance for Clinical Laboratory.

Efficacy AssessmentsClinic Blood Pressure Measurements

Trained study personnel measured BP at the clinicby use of a standard mercury sphygmomanometer withthe appropriate cuff size. BP measurement was carriedout at �24 hours after the administration of the studydrug on the previous day to ensure trough measure-ment. Patients were seated for �5 minutes and re-frained from smoking and ingesting caffeine during the
30 minutes prior to the measurement. At the first visit,
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the left or right arm with the higher reading was se-lected, and all subsequent measurements were made onthat arm. BP readings were rounded to the nearest evennumber, and the average of 2 readings taken 2 minutesapart was recorded. The first and fifth Korotkoffsounds were regarded as SBP and DBP measurements,respectively.

Ambulatory Blood Pressure MonitoringIn study 1, 24-hour ABPM (Tonoport V, GE

Healthcare) was performed before (baseline) and after4 weeks of treatment. After patients reported to theclinic in the morning, ABPM was started and was con-tinued for the subsequent 24 hours. The interval ofmeasurements was 30 minutes during the day (6 AM–0 PM) and 1 hour during the night (10 PM–6 AM theext day). Patients were informed of the possible prob-

ems related to ABPM and were instructed how to stopBPM in the event of a problem. Patients were also

nstructed to record daily events and were discouragedrom engaging in strenuous physical activities. Read-ngs of SBP �70 or �250 mm Hg and DBP �40 or�150 mm Hg were discarded, and daytime BP wasaveraged over a 1-hour period. BP was then synchro-nized (ie, matched by measurement time) in each pa-tient, and 4-week values were subtracted from baselinevalues to determine mean changes in 24-hour, daytime,and nighttime BP.

In addition, the trough-to-peak (T/P) ratio was de-rived to characterize the sustained BP-lowering profileof the study drug toward the end of the dosing interval.Peak effect was defined as the maximal decrease in BPfrom baseline over any 1-hour period after drug ad-ministration using 2-hour moving averages.13 Simi-arly, the trough effect was defined as the maximalecrease in BP from baseline over the last 2 hours ofosing interval (ie, 22–24 hours postdose). T/P ratio issigned variable, and any value greater than zero

ndicates that BP-lowering efficacy is maintained atrough as long as the trough and the peak are nega-ive (ie, reduction from baseline). However, if bothalues are positive, suggesting treatment failure overhe entire dosing interval, the T/P ratio can be �1,hich is meaningless and misleading. To avoid thisitfall, T/P ratio was not defined in this case, ensur-ng a maximum T/P ratio of 1. T/P ratio analysis waserformed on data from individual patients androm all patients as previously recommended for a
ingle effect profile.14,15 m
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End PointsMean changes in sitting DBP from baseline to 4

weeks (study 1) and 8 weeks (study 2) were the primaryefficacy end points. Secondary efficacy end points instudy 1 were changes from baseline to week 4 in sittingSBP and mean arterial pressure (MAP), calculated asDBP � (SBP – DBP)/3. In study 2, the following sec-ondary end points were measured: changes in sittingDBP from baseline to weeks 2 and 4; changes in sittingSBP from baseline to weeks 2, 4 and 8; and the propor-tion of responders (defined as those with a sitting DBP�90 mm Hg or a change from baseline in sitting DBP�–10 mm Hg) at week 8. For 24-hour ABPM data(study 1), change from baseline to week 4 in 24-hour,daytime, and nighttime mean SBP and DBP values, andT/P ratio, were additional efficacy outcomes.

Tolerability AssessmentSafety profile end points were TEAEs, defined as any

untoward events not present prior to the administra-tion of the study drug, or already present but thatworsened in intensity or in frequency during treatment.TEAEs included abnormalities found on clinical labo-ratory testing, physical examination, and/or ECGreadings.

Statistical AnalysisNo formal sample size estimation was carried out in

study 1 due to its pilot and exploratory nature. None-theless, it was calculated that 15 patients per group (ie,60 in total for 4 groups) would be necessary to detect aclinically meaningful between-group difference inmean (SD) change from baseline in sitting DBP of �7(6) mm Hg using the Dunnett test,16 which adjusts a% significance level for multiple comparisons, with aower of 80% and an anticipated dropout rate of0%. In study 2, the required number of patients wasstimated using the Williams test17 to determine theinimum effective dose of fimasartan compared withlacebo. Assuming a clinically meaningful between-roup difference in mean (SD) change from baseline initting DBP of 8 mm Hg (SD 10.6, the most conserva-ive value in study 1) after 8 weeks of treatment, it wasalculated that a sample size of 29 patients per group,r a total of 145 patients for 5 treatment groups, woulde needed to provide a power of 80% at a 1-sidedignificance level of 2.5%. A higher dropout rate of0% was assumed in study 2, given its longer treat-
ent duration compared with that of study 1 (ie, 8 vs
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4 weeks), so a total of 182 patients was planned forenrollment.

Equality for baseline characteristics among groupswas tested using ANOVA, Kruskal-Wallis test, or �2

test depending on the nature of each variable. Contin-uous efficacy end points were analyzed using ANOVA,followed by the Dunnett procedure to compare pla-cebo as the control and each of the fimasartan doseswhile adjusting multiplicity. Further pairwise compar-isons were made using the 2-sample t test with theBonferroni correction (study 1) or the all-pairwiseTukey method (study 2). Nonparametric tests such asthe Wilcoxon rank sum test were also used whendeemed necessary. A �2 test was used to determine

hether there were significant differences amongroups in the proportions of responders (study 2). Inddition, the Williams test was used for characterizinghe monotonically increasing or decreasing trend in theose-response relationship of fimasartan. The frequen-ies of AEs, including laboratory abnormalities, wereompared among the treatment groups using the �2

test.Intent-to-treat without last observation carried for-

ward (LOCF) was the primary statistical analysis pop-ulation. All randomized patients with data availablefrom �1 efficacy assessment were included in the effi-cacy analysis, whereas the safety profile analysis in-volved all patients who had taken �1 dose of studydrug. An additional LOCF analysis was performed ondata from clinic BP measurements, in which data fromthose who dropped out were carried forward beyondthe point at which the last data were available. Thelevel of statistical significance was 0.05 (2-sided), un-less noted otherwise, and SAS version 9.1.3 (SAS Insti-tute Inc) was used for statistical data analysis.

RESULTSStudy Population

Sixty-one patients participated in study 1 (April2005–June 2006), and 52 participants (85.2%) com-pleted 4-week treatment; study 2 (October 2007–June2008) randomized 195 patients, 169 (86.7%) of whomfinished 8 weeks of treatment (Figure 1). The 221 pa-tients who completed study were included in the effi-cacy analysis. ABPM data were obtained from a totalof 45 (73.8%) patients in study 1, comprising theABPM efficacy analysis population. One patient in thefimasartan 180-mg group in study 1 did not take
the study drug; therefore, this patient was excluded
June 2012

from the safety profile analysis population, which con-sisted of the remaining 225 participants.

The treatment groups in each study were compara-ble for all baseline demographic and clinical character-istics (Table I). The mean age of each treatment groupranged from 50.0 to 55.1 years, and the overall pro-portion of male patients was 68%. The mean ranges ofbaseline DBP and SBP were 98.7 to 103.6 mm Hg and147.0 to 158.1 mm Hg, respectively. In both studies,patients had been treated, prior to enrollment, mostfrequently with calcium channel blockers, angiotensin-converting enzyme inhibitors, and ARBs. No abnor-mal laboratory values were noted at baseline in eitherstudy.

EfficacyFimasartan was associated with significant reduc-

tions in DBP, SBP, and MAP after 4-week treatment(study 1). Mean changes in sitting DBP and MAP weresignificantly greater in the 180-mg group than in theplacebo group (�16.4 vs �5.5 mm Hg [P � 0.022] and�19.2 vs �7.5 mm Hg [P � 0.038], respectively)(Table II). The mean reductions in sitting DBP, SBP,and MAP in the fimasartan 20- and 60-mg groups werealso 5.7 to 10.5 mm Hg greater than those in the pla-cebo group, but these differences failed to reach statis-tical significance.

The BP-lowering efficacy of fimasartan was alsofound in the longer-term study 2. For example, BP waslowered with fimasartan use as early as after 2 weeks oftreatment, reached the maximum decrease at week 4,with the decrease maintained until week 8 (Table III).Eight-week treatment with fimasartan 60, 120, and240 mg was associated with significant reductions insitting DBP and SBP compared with placebo, with themean of each reduction ranging from �6.9 to �8.6mm Hg and from �10.1 to �12.8 mm Hg, respectivelyP � 0.0001–� 0.005). In addition, significantlyreater proportions of patients responded to treatmentith fimasartan 60 mg (76.3%), 120 mg (68.4%), and40 mg (67.6%) than with placebo (31.7%) (P �.01–� 0.05) (Figure 2).

Similar findings were noted in the LOCF analyses inoth studies. On LOCF analysis in study 1, mean (SD)eductions from baseline to 4 weeks in sitting DBPere significant with all of the fimasartan doses (20g, �11.9 [6.6] mm Hg [P � 0.0001]; 60 mg, �11.6

[10.3] mm Hg [P � 0.0006]; 180 mg, �15.9 [11.8]
mm Hg [P � 0.0001]). The decrease in the placebo
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Assessed foreligibility (N = 81)

Excluded during screening (n = 20)Did not meet inclusion criteria (n = 16)

Declined to participate (n = 3)Other (n = 1)

Randomized (n = 61)

Placebo (n = 15)Took as (n = 15) Included in safety analysis (n = 15)

Placebo (n = 41)Took as assigned (n = 41)

Included in safety analysis (n = 41)

Fimasartan 20 mg (n = 16)Took as assigned (n = 16)


Fimasartan 20 mg (n = 41) Took as

assigned (n = 41) Included in safety analysis (n = 41)







Fimasartan 60 mg (n = 15)Took asassigned (n = 15)


Fimasartan 180 mg (n = 15) Took as assigned (n = 14)


Dropped out (n = 4)Consent withdrawn (n = 2)

Adverse event (n = 1)Protocol violation (n = 1)

Dropped out (n = 4)Protocol violation (n = 2)Lost to follow-up (n = 1)

Other (n = 1)


Adverse event (n = 1)Protocol violation (n = 1)

Other (n = 1)

Dropped out (n = 8)Consent withdrawn (n = 1)Protocol violation (n = 1)Lost to follow-up (n = 1)

Dropped out (n = 8)Protocol violation (n = 6)

Consent withdrawn (n = 1)Treatment failure (n = 1)

Dropped out (n = 5)Lost to follow-up (n = 2)Treatment failure (n = 1)Protocol violation (n = 1)

Other (n = 1)

Completed & included in efficacy

analysis (n = 36 [88%])


analysis (n = 33 [80%])


analysis (n = 35 [92%])


analysis (n = 32 [84%])


analysis (n = 33 [89%])

Dropped out (n = 1)Adverse event (n = 1)


Dropped out (n = 2)Treatment failure (n = 1)

Consent withdrawn (n = 1)

Completed & included in efficacy analysis

(n = 13 [87%]) (11 for ABPM)


(n = 14 [88%]) (13 for ABPM)


(n = 14 [93%]) (13 for ABPM)

Assessed foreligibility (N = 272)

Randomized (n = 195)

Excluded during screening (n = 77)Did not meet inclusion criteria (n = 77)


(n = 11 [73%]) (8 for ABPM)

Study 2

Study 1

Figure 1. Flow diagram of participants in studies 1 and 2 of the efficacy and tolerability of fimasartan in Koreanpatients with essential hypertension.

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group was �5.7 (9.5) mm Hg (P � 0.0373), resultingin a statistically significant placebo-adjusted mean dif-ference of �10.2 mm Hg (95% CI, �18.7 to �1.7 mmHg; P � 0.0151) with fimasartan 180 mg, similar to�10.8 mm Hg (95% CI, �20.3 to �1.3 mm Hg; P �0.022) in a non-LOCF analysis (Table II). Likewise,the mean placebo-adjusted reductions in sitting DBPand SBP with fimasartan 60, 120, and 240 mg in study2 ranged from �6.4 to �8.1 mm Hg and from �10.5to �11.3, respectively (P � 0.0001–� 0.005), which

ere also similar to the findings on non-LOCF analy-is, as summarized in Table III.

Fimasartan 20 mg was not associated with signifi-ant reductions in placebo-adjusted sitting DBP at

Table I. Baseline demographic and clinical characteriand tolerability of fimasartan in Korean patieotherwise specified.*

Characteristic

Study 1

Fimasartan

Plac(n �

20 mg(n � 16)

60 mg(n � 15)

180 mg(n � 15)

DemographicsAge, y 55.1 (17.7) 50.6 (7.1) 53.1 (6.1) 50.0Male sex, no. (%) 9 (56.3) 10 (66.7) 7 (46.7) 13

Physical examinationWeight, kg 66.9 (12.4) 71.7 (9.4) 66.4 (11.4) 69.8BMI, kg/m2 25.4 (3.4) 26.2 (3.0) 25.7 (2.9) 25.6BP, mm Hg

Systolic 157.8 (16.4) 158.1 (15.9) 152.0 (13.8) 152.9Diastolic 103.3 (5.4) 102.4 (5.1) 103.1 (4.9) 103.6

HistorySmoking status

Current NA NA NA NHistory NA NA NA N

Medication history† 10 (62.5) 11 (73.3) 10 (66.7) 10CCB 9 (56.3) 4 (26.7) 5 (33.3) 6ACE inhibitor orARB 4 (25.0) 4 (26.7) 8 (53.3) 9�-Blocker 2 (12.5) 4 (26.7) 2 (13.3) 3Diuretic 3 (18.8) 4 (26.7) 4 (26.7) 6Other 1 (6.3) — — —

Laboratory valuesTC, mg/dL 204.1 (36.7) 205.3 (33.9) 204.8 (30.1) 197.3AST, IU/L 25.4 (13.9) 26.1 (5.3) 26.6 (7.8) 24.3ALT, IU/L 32.6 (23.9) 32.0 (15.0) 33.5 (19.3) 27.1SCr, mg/dL 0.9 (0.2) 1.0 (0.2) 0.9 (0.2) 1.1

ACE � angiotensin converting enzyme; ALT � alanine aminotransferase; ARBmass index; BP � blood pressure; CCB � calcium channel blocker; NA � no*No significant differences were noted between treatment groups in either st†Antihypertensive medications taken within 12 weeks before eligibility assessm

eek 8 (Table III). Moreover, the proportion of re- r

June 2012

ponders in the fimasartan 20-mg group was not sig-ificantly different from the that of the placebo group43.9% vs 31.7%; P � 1.00) (Figure 2), whereas theifference between fimasartan 60 and 20 mg was sig-ificant (76.3% vs 43.9%; P � 0.05). To reflect thesendings, 60 mg was identified as the minimum effectiveose (P � 0.00016; Williams test) for the monotoni-ally increasing dose-response relationship of fimasar-an. However, the magnitude of BP reduction and theroportions of responders were not markedly differentetween the fimasartan 60-, 120-, and 240-mg doses,ncluding sitting SBP with fimasartan 20 mg. Further-ore, no significant differences in changes from base-

ine in sitting DBP and SBP or in the proportion of

of the population in this pair of studies of the efficacyith essential hypertension. Data are mean (SD) unless

Study 2

Fimasartan

Placebo(n � 41)

20 mg(n � 41)

60 mg(n � 38)

120 mg(n � 38)

240 mg(n � 37)

53.2 (9.0) 53.4 (9.0) 52.6 (10.7) 52.8 (10.5) 53.4 (8.7)26 (63.4) 29 (76.3) 31 (81.6) 27 (73.0) 22 (53.7)

69.9 (9.7) 69.2 (10.6) 71.0 (9.6) 69.8 (9.3) 67.2 (10.7)25.7 (3.2) 24.6 (2.6) 25.1 (2.3) 25.0 (2.5) 25.1 (2.7)

150.4 (13.6) 147.0 (11.7) 148.9 (12.7) 151.4 (16.6) 150.1 (16.0)99.2 (6.0) 100.1 (5.6) 98.7 (5.8) 100.2 (6.0) 99.6 (4.9)

3 (7.3) 7 (18.4) 9 (23.7) 7 (18.9) 3 (7.3)12 (29.3) 7 (18.4) 14 (36.8) 7 (18.9) 11 (26.8)27 (65.9) 24 (63.2) 23 (60.5) 22 (59.5) 29 (70.7)20 (48.8) 17 (44.7) 17 (44.7) 16 (43.3) 22 (53.7)

13 (31.7) 10 (26.3) 8 (21.1) 9 (24.3) 12 (29.3)10 (24.4) 4 (10.5) 3 (7.9) 2 (5.4) 4 (9.8)

4 (9.8) 3 (7.9) 4 (10.5) 2 (5.4) 2 (4.9)— — 2 (5.3) — —

195.5 (33.8) 196.9 (33.4) 197.3 (35.2) 185.0 (30.2) 190.5 (40.0)25.3 (8.5) 24.3 (11.1) 23.4 (6.9) 24.7 (7.7) 22.2 (6.4)28.3 (16.9) 25.1 (15.6) 26.2 (14.6) 29.1 (18.1) 22.3 (11.4)

1.0 (0.2) 1.0 (0.1) 1.0 (0.2) 0.9 (0.2) 0.9 (0.2)

iotensin II receptor blocker; AST � aspartate aminotransferase; BMI � bodyble; SCr � serum creatinine; TC � total cholesterol.OVA, Kruskal-Wallis, or �2 test).

sticsnts w

ebo15)

(12.0)(86.7)

(7.8)(2.4)

(12.3)(4.2)

AA(66.7)(40.0)

(60.0)(20.2)(40.0)

(39.9)(7.6)(14.1)(0.3)

� angt availaudy (AN

ent.

esponders were noted among any of the fimasartan

1279

�lmsfitaHas

td

lbwicipeddtHawr

r(I


doses (pairwise Tukey test), with the exception of thedifference in the proportion of responders between thefimasartan 20- and 60-mg groups, as described earlier.

After 4-week treatment, fimasartan 20, 60, and 180mg once daily were associated with significant reduc-tions in mean 24-hour, daytime, and nighttime DBPand SBP (ranges, �5.9 to �11.4 mm Hg and �12.2 to

20.2 mm Hg, respectively). These measures, particu-arly mean nighttime DBP (6.0 mm Hg) and SBP (8.1m Hg), were increased with placebo use, resulting in

ignificant differences between placebo and each of themasartan doses (P � 0.001–� 0.05) (Figure 3). Fur-hermore, the reductions in mean 24-hour, daytime,nd nighttime SBP in the 180-mg group were 26.1 mmg—65.3% greater than in the 20- or 60-mg group,

lthough these differences were not statisticallyignificant.

This BP-lowering effect of fimasartan was main-ained over the full 24-hour dosing interval with all

Table II. Changes from baseline in blood pressure (Bthis pair of studies of the efficacy and tolhypertension. Data are mm Hg.

BP Measure20 mg

(n � 14)

Sitting DBPMean (SD) �11.4* (6.8) �11.2Difference vs placebo,LSM (95% CI) �5.9 (�14.8 to 3.0) �5

Sitting SBPMean (SD) �21.3� (17.4) �21.Difference vs placebo,LSM (95% CI) �10.0 (�26.6 to 6.6) �10

Sitting MAPMean (SD) �14.7* (8.9) �14.8Difference vs placebo,LSM (95% CI) �7.3 (�17.7 to 3.2) �7

DBP � diastolic BP; LSM � least squares mean; MAP � mesystolic BP.*P � 0.0001 versus baseline (paired t test).†P � 0.005 versus baseline (paired t test).‡P �0.0005 versus baseline (paired t test).§P � 0.022 versus placebo (Dunnett procedure for multiple�P � 0.001 versus baseline (paired t test).¶P � 0.038 versus placebo (Dunnett procedure for multiple

oses of fimasartan. Fimasartan was associated with g

1280

owered BP toward the end of the dosing intervalased, on the hourly mean BP changes from baseline toeek 4 (Figure 4). In the 20-mg group, there was no dip

n DBP after administration, and there was an upwardonvex curve in SBP values. Despite these unusual find-ngs, fimasartan was associated with a BP-loweringrofile distinctive from placebo, which had no appar-nt BP-lowering effect, particularly at the end of theosing interval. Likewise, fimasartan, irrespective ofose, was associated with significantly greater reduc-ions in mean trough DBP (�9.2, �7.7, and �12.1 mmg with 20, 60, and 180 mg once daily, respectively)

nd SBP (�20.3, �9.5, and �21.2 mm Hg), comparedith placebo (4.6 and 10.1 mm Hg for DBP and SBP,

espectively) (P � 0.005–� 0.05) (Table IV).These findings were in agreement with the high T/P

atios of fimasartan, which ranged from 0.41 to 0.98all patients) and from 0.14 to 0.47 (individual) (TableV). Moreover, these T/P ratios in the fimasartan

ter 4 weeks of treatment with fimasartan (study 1) inlity of fimasartan in Korean patients with essential

asartan

Placebo(n � 13)

mg14)

180 mg(n � 11)

.6) �16.4‡ (10.4) �5.5 (10.1)

4.6 to 3.2) �10.8§ (�20.3 to �1.3) —

.8) �24.8‡ (14.6) �11.3 (20.4)

7.2 to 6.1) �13.5 (�31.2 to 4.2) —

.7) �19.2‡ (11.0) �7.5 (13.1)

7.8 to 3.2) �11.7¶ (�22.9 to �0.6) —

erial pressure (calculated as DBP � [SBP – DBP]/3); SBP �

arisons).

arisons).

P) aferabi

Fim

60(n �

† (10

.7 (�1

9� (17

.5 (�2

‡ (11

.3 (�1

an art

comp

comp

roups were significantly or numerically higher than

Volume 34 Number 6

H. Lee et al.

Table III. Changes from baseline in blood pressure (BP), by treatment week (study 2) in this pair of studies of theefficacy and tolerability of fimasartan in Korean patients with essential hypertension. Data are mm Hg.

BP Measures Week 2 Week 4 Week 8

Sitting SBP20 mg, no. of patients 37 34 33

Mean (SD) �12.9a (12.4) �17.5a (11.7) �17.4a (13.7)Difference vs placebo, LSM(95% CI) �7.4 (�14.6 to �0.2) �13.8 (�21.2 to �6.4) �10.7d (�18.1 to �3.4)

60 mg, no. of patients 38 38 35Mean (SD) �15.3a (11.6) �16.6a (12.7) �17.5a (10.4)Difference vs placebo, LSM(95% CI) �9.8d (�16.9 to �2.7) �12.9 (�20.1 to �5.8) �10.8d (�18.1 to �3.6)

120 mg, no. of patients 37 34 33Mean (SD) �13.8a (14.4) �17.6a (13.9) �16.8a (14.3)Difference vs placebo, LSM(95% CI) �8.3b (�15.4 to �1.1) �13.9c (�21.3 to �6.6) �10.1d (�17.4 to �2.7)

240 mg, no. of patients 37 35 33Mean (SD) �12.2a (13.9) �17.0a (13.9) �19.5a (12.5)Difference vs placebo, LSM(95% CI) �6.7 (�13.9 to 0.5) �13.3c (�20.6 to �6.0) �12.8c (�20.1 to �5.4)

Placebo 38 38 36Mean (SD) �5.5e (10.4) �3.7f (10.9) �6.7g (10.4)

Sitting DBP20 mg, no. of patients 37 34 33

Mean (SD) �5.8a (7.4) �9.4a (6.3) �9.7a (8.0)Difference vs placebo, LSM(95% CI) �1.2 (�5.5 to 3.0) �6.1d (�10.3 to �1.9) �3.9 (�8.7 to 0.9)

60 mg, no. of patients 38 38 35Mean (SD) �11.5a (7.3) �12.0a (6.6) �14.4a (7.9)Difference vs placebo, LSM(95% CI) �6.9c (�11.2 to �2.7) �8.6c (�12.7 to �4.5) �8.6c (�13.3 to �3.9)

120 mg, no. of patients 37 34 33Mean (SD) �8.7a (8.9) �11.9a (8.0) �14.1a (8.0)Difference vs placebo, LSM(95% CI) �4.1 (�8.4 to 0.2) �8.6c (�12.8 to �4.4) �8.4c (�13.2 to �3.7)

240 mg, no. of patients 37 35 33Mean (SD) �8.9a (6.7) �12.0a (8.5) �12.7a (7.3)Difference vs placebo, LSM(95% CI) �4.3b (�8.6 to �0.1) �8.7c (�12.9 to �4.5) �6.9d (�11.7 to �2.1)

Placebo 38 38 36Mean (SD) �4.6h (7.2) �3.3e (6.7) �5.8h (8.8)

DBP � diastolic BP; LSM � least squares mean; SBP � systolic BP.aP � 0.0001 versus baseline (paired t test).bP � 0.05 versus placebo (Dunnett test for multiple comparisons).cP � 0.0001 versus placebo (Dunnett test for multiple comparisons).dP � 0.005 versus placebo (Dunnett test for multiple comparisons).eP � 0.005 versus baseline (paired t test).fP � 0.05 versus baseline (paired t test).gP � 0.001 versus baseline (paired t test).hP � 0.0005 versus baseline (paired t test).

June 2012 1281

th

Ti

citr[

c


those in the placebo group, which had negative meanT/P ratios for DBP and SBP, both globally and individ-ually, because many patients in the placebo groupfailed in sustaining reduced BP at trough, resulting in ahigher-than-baseline trough BP after treatment whilethe peak change was negative (ie, positive divided bynegative becoming negative). Furthermore, T/P ratioscould not be determined in 3 patients in the placebogroup because their peaks and troughs were all positive(ie, treatment failure throughout the dosing interval).Therefore, the reported T/P ratios for placebo in TableIV are biased to its favoring side, and the difference inhe T/P ratios between placebo and fimasartan couldave been greater.

TolerabilityThe proportions of patients who experienced �1

EAE were comparable among the treatment groupsn both studies (P � 0.5474 and 0.6222 in studies 1and 2, respectively [�2 test]) (Table V). Moreover, AEsonsidered treatment related occurred most frequentlyn the placebo group in both studies, although the be-ween-treatment difference in proportions did noteach significance in either study (study 1, P � 0.5456

10090

80

70

60

50

40302010

0

43.9

†* †‡

76.368.4 67.6

20 mg 60 mg

Once-Daily Fimasartan Dose

120 mg 240 mg Placebo

Prop

ortio

n of

Res

pond

ers

(%)

31.7

Figure 2. Proportions (95% CI) of responders af-ter 8 weeks of treatment (study 2) in thispair of studies of the efficacy and tolera-bility of fimasartan in Korean patientswith essential hypertension. *P � 0.05versus 20 mg; †P� 0.01 versus placebo;‡P � 0.05 versus placebo (all, stepdownBonferroni-corrected multiple compari-sons test).

Fisher exact test]; study 2, P � 0.6241 [�2 test]). No

1282

serious TEAEs were reported in either study, and allTEAEs resolved eventually without treatment.

Headache and dizziness were the 2 most frequentlyreported TEAEs in studies 1 and 2 combined (9.8%and 4.4%, respectively). Two patients in the 240-mggroup (study 2) developed elevated AST and ALT. El-evated liver enzymes were found in a total of 8 patients(3.1%), 5 of whom received fimasartan 240 mg and 1each of whom received fimasartan 60 mg, fimasartan120 mg, and placebo. However, the difference was notstatistically significant among the treatment groups.Liver enzymes returned to normal without anyintervention.

DISCUSSIONIn the present studies, fimasartan was associated withsignificantly decreases in BP in patients with hyperten-sion, the magnitude of which was also significantlygreater than with placebo. This BP-lowering efficacy offimasartan compared with placebo has been repeatedlyreported in various settings: clinic BP measurement af-ter 4 weeks and at 2 to 8 weeks, and 24-hour ABPMmeasurement after 4 weeks. The antihypertensive ef-fect of fimasartan was apparent as early as after 2weeks of treatment, with the maximum decreasereached within 4 weeks. The time to maximum effectwas generally in line with those reported with otherARBs (4–6 weeks with candesartan,18 eprosartan,19,20

irbesartan,21,22 and valsartan20; and 3–6 weeks withlosartan23).

The collective evidence suggests that 60 mg may bethe minimum effective dose of fimasartan. A clear de-marcation between fimasartan 20 and 60 mg noted inthe large-scale, longer-term study 2 supports this no-tion, although the difference in efficacy between these 2doses was not obvious in the small-scale, shorter-termstudy 1. Fimasartan also had a flat dose-response rela-tionship, particularly at doses �60 mg. Findings fromvarious efficacy measures were not significantly differ-ent among the fimasartan groups. These findings com-pare well with those of several other ARBs, for which aflat dose-response relationship has been reported, in-cluding eposartan,24 losartan,25–27 and telmisar-tan.25,28 A flat dose-response curve is considered typi-al of the dose-response relationship of the ARBs.29

However, it is too early at this point to squarelyconclude that fimasartan doses �60 mg would be nomore effective than 60 mg because some patients may
benefit from these higher doses. In nonresponders, the
Volume 34 Number 6

H. Lee et al.

B

A

24-Hour Mean

15

10

52.0

0.2

6.0

0

–5

–10–9.5‡

–10.7* –9.7§–10.1§

–10.9§–11.4§

–5.9§

–7.9‡

–10.2*

–15

–20

20

15

10

5

0

–5

–10

–15

–20

4.42.7

8.1

–14.7*–14.1*

–19.6†

–13.5†–12.2†

–20.2†

–15.1‡ –14.7‡

–19.1*

–25

–30

–35

Cha

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(mm

Hg)

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Blo

od P

ress

ure

(mm

Hg)

Daytime Mean Nighttime Mean

24-Hour Mean Daytime Mean Nighttime Mean

Placebo20 mg 60 mg 180 mg

Placebo20 mg 60 mg 180 mg

Figure 3. Least squares mean (95% CI) changes from baseline to 4 weeks in mean 24-hour, daytime, andnighttime systolic (A) and diastolic (B) blood pressure by 24-hour ambulatory blood pressure moni-toring (study 1) in this pair of studies of the efficacy and tolerability of fimasartan in Korean patientswith essential hypertension. *P � 0.005, †P � 0.001, ‡P � 0.01, and §P � 0.05 versus placebo(Dunnett test for multiple comparisons).

June 2012 1283


15

10

5

0

–5

–10

–15

–20

0 2 4 6 8 10 12 14 16 18 20 22 24Time After Dose (h)

Cha

nge

from

Bas

elin

e in

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ure

(mm

Hg)

20

A

B

10

15

5

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–5

–10

–15

–20

–25

–30

–35

–40

0 2 4 6 8 10 12 14 16 18 20 22 24Time After Dose (h)

Cha

nge

from

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e in

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(mm

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10

15

5

0

–5

–10

–15

–20

–25

–30

–35

–40

0 2 4 6 8 10 12 14 16 18 20 22 24Time After Dose (h)

15

10

5

20 mg , placebo-adjusted60 mg, placebo-adjusted180 mg, placebo-adjusted

20 mg , placebo-adjusted60 mg, placebo-adjusted180 mg, placebo-adjusted

0

–5

–10

–15

–20

0 2 4 6 8 10 12 14 16 18 20 22 24Time After Dose (h)

Placebo

20 mg60 mg180 mg

Placebo

20 mg60 mg180 mg

Figure 4. Hourly mean systolic (A) and diastolic (B) blood pressure (BP) changes from baseline after 4-weektreatment by 24-hour ambulatory BP monitoring (study 1). Placebo-adjusted net effects (right) wereobtained by subtracting mean changes from baseline in the placebo group from correspondingchanges in each fimasartan dose group. Locally weighted scatterplot smoothing trend lines are overlaidfor easier comparison among the treatment groups. The global estimates for trough and peak in TableIV were determined from the curves (left).

1284 Volume 34 Number 6

H. Lee et al.

Table IV. Secondary efficacy end points based on 24-hour ambulatory blood pressure (BP) monitoring after 4weeks of treatment with fimasartan (study 1) in this pair of studies of the efficacy and tolerability offimasartan in Korean patients with essential hypertension.*

End Point/Estimation Method

Fimasartan

Placebo(n � 11)

20 mg(n � 13)

60 mg(n � 13)

180 mg(n � 8)

SBPTrough, mm Hg

IndividualMean (SD) �20.3† (12.3) �9.5‡ (22.2) �21.2† (22.1) 10.1 (20.2)95% CI �27.8 to �12.9 �22.9 to 3.9 �41.7 to �0.7 �3.5 to 23.6

GlobalMean �20.3 �9.5 �21.2 10.195% CI �25.6 to �15.1 �18.4 to �0.6 �33.6 to �8.8 0.9 to 19.2

Peak, mm HgIndividual

Mean (SD) �43.8‡ (9.7) �40.0§ (23.7) �44.5‡ (16.3) �21.7 (24.1)95% CI �49.6 to �37.9 �54.3 to �25.7 �58.1 to �30.8 �37.9 to �5.5

GlobalMean �20.8 �23.3 �28.3 �4.995% CI �28.9 to �12.7 �38.0 to �8.7 �43.4 to �13.1 �20.3 to 10.4

Time to peak, hIndividual

Mean (SD) 9.1 (7.0) 9.4 (7.3) 11.9 (5.7) 9.9 (6.7)95% CI 4.9 to 13.3 5.0 to 13.8 7.1 to 16.6 5.4 to 14.4

Global, mean 23.0 7.0 8.0 3.0T/P ratio

IndividualMean (SD) 0.47� (0.29) 0.14 (0.30) 0.36¶ (0.50) �0.25 (0.91)95% CI 0.29 to 0.64 �0.05 to 0.32 �0.11 to 0.83 �0.96 to 0.45

Global, mean 0.98 0.41 0.75 �2.04

DBPTrough, mm Hg

IndividualMean (SD) �9.2‡ (10.7) �7.7‡ (8.7) �12.1� (13.1) 4.6 (12.1)95% CI �15.7 to �2.7 �12.9 to �2.4 �24.3 to 0.0 �3.5 to 12.7

GlobalMean �9.2 �7.7 �12.1 4.695% CI �13.5 to �4.8 �11.3 to �4.0 �19.6 to �4.6 �1.0 to 10.2

Peak, mm HgIndividual

Mean (SD) �29.2‡ (9.2) �27.9‡ (10.5) �28.4‡ (11.7) �15.8 (12.1)95% CI �34.8 to �23.6 �34.2 to �21.5 �38.2 to �18.6 �23.9 to �7.6

GlobalMean �15.6 �15.8 �17.0 �4.095% CI �24.0 to �7.3 �24.7 to �7.0 �25.9 to �8.2 �14.2 to 6.1

Time to peak, hIndividual

Mean (SD) 7.8 (5.8) 9.3 (7.1) 13.1 (8.5) 10.5 (8.6)95% CI 4.3 to 11.3 5.0 to 13.6 6.0 to 20.2 4.8 to 16.3

Global, mean 4.0 5.0 13.0 2.0T/P ratio

IndividualMean (SD) 0.30‡ (0.35) 0.28‡ (0.31) 0.45‡ (0.47) �0.58 (1.31)95% CI 0.08 to 0.51 0.10 to 0.47 0.01 to 0.88 �1.52 to 0.36

Global, mean 0.59 0.48 0.71 �1.13

DBP � diastolic BP; SBP � systolic BP; T/P � trough-to-peak.*Global estimates were derived using data from all patients combined (Figure 4). Statistical testing was not applicable to global estimates.†P � 0.005 versus placebo (Dunnett procedure for multiple comparisons).‡P � 0.05 versus placebo (Dunnett procedure for multiple comparisons).§P � 0.07 versus placebo (Dunnett procedure for multiple comparisons).�P � 0.01 versus placebo (Dunnett procedure for multiple comparisons).¶P � 0.0622 versus placebo (Dunnett procedure for multiple comparisons).

June 2012 1285

A

wpdtTmTcmt


dose may be doubled for an added BP reduction; thispractice was not tested in the present studies. In severaldose-ranging studies of other ARBs, uptitration wasassociated with a substantial additional BP reduc-tion.30 One of the next steps for fimasartan develop-ment should be to investigate whether dose doubling orother methods of uptitration of dose could lower BP inpatients who do not respond to fimasartan treatmentafter a certain period of time (eg, 4 weeks).

The findings from the present studies also suggestthat fimasartan maintained BP reductions through-out the full 24 hours based on the 24-hour ABPMdata. This sustained efficacy of fimasartan over thedosing interval, especially at trough, was studied in 2ways. First, hourly mean BP changes from baseline 4weeks of treatment were flat, resulting in downwardconcave curves in the fimasartan groups, with the

Table V. Treatment-emergent adverse events (TEAEs)tolerability of fimasartan in Korean patienpatients.

TEAE

Study 1

Fimasartan

(20 mg

(n � 16)60 mg

(n � 15)180 mg

(n � 14)

Patients with �1 TEAE* 10 (62.5) 9 (60.0) 11 (78.6)Patients with �1 TEAE consideredtreatment related† 2 (12.5) 3 (20.0) 2 (14.3)TEAE

Headache 4 (20.0) 5 (33.3) 3 (21.4)Elevated CPK 2 (12.5) 1 (6.7) 1 (7.1)Rhinorrhea 2 (12.5) 1 (6.7) 2 (14.3)Productive cough 2 (12.5) 1 (6.7) 1 (7.1)Cough 2 (12.5) 1 (6.7) 0Flushing 2 (12.5) 1 (6.7) 0Pruritus 1 (6.3) 1 (6.7) 1 (7.1)Abdominal pain, upper 1 (6.3) 0 1 (7.1)Dyspepsia 1 (6.3) 0 0Dizziness 0 1 (6.7) 2 (14.3)Musculoskeletal stiffness 0 1 (6.7) 0Nasopharyngitis 0 1 (6.7) 0Nausea 0 1 (6.7) 0Diarrhea 0 0 2 (14.3)Chest pain 0 0 1 (7.1)Elevated ALT 0 0 0URTI 0 0 0Palpitations 0 0 0Elevated AST 0 0 0

ALT � alanine aminotransferase; AST � aspartate aminotransferase; CPK �*P � 0.5474 and 0.6222 for studies 1 and 2, respectively (�2 test).†P � 0.5456 (study 1; Fisher’s exact test) and P � 0.6241 (study 2; �2 test).‡These 2 patients also experienced elevated ALT.

exception of the 20-mg group. Second, T/P ratios f

1286

were significantly greater with fimasartan than pla-cebo, and these values approximated or were greaterthan 0.5, which is the lower limit for approval ofantihypertensive drugs administered once daily inKorea31 (the lower limit of the US Food and Drug

dministration is less strict32).In the present studies, treatment with fimasartan

as well tolerated for up to 8 weeks in these Koreanatients with hypertension. There were no significantifferences between fimasartan and placebo in terms ofhe proportions of patients experiencing TEAEs, andEAEs considered treatment related were less com-only reported in the fimasartan groups. All of theEAEs, with headache and dizziness being the mostommonly reported in both studies combined, wereild to moderate and resolved eventually without

reatment. These findings are in agreement with the

a rate of �1% in this pair of studies of the efficacy andth essential hypertension. Data are number (%) of

Study 2

Total(n � 255))

Fimasartan

Placebo(n � 41)

20 mg(n � 41)

60 mg(n � 38)

120 mg(n � 38)

240 mg(n � 37)

) 10 (24.4) 12 (31.6) 10 (26.3) 14 (37.8) 15 (36.6) 99 (44.0)

) 4 (9.8) 6 (15.8) 4 (10.5) 7 (18.9) 8 (19.5) 41 (16.1)

) 2 (4.9) 3 (7.9) 0 0 2 (4.9) 22 (9.8)0 1 (2.6) 0 1 (2.7) 1 (2.4) 7 (3.1)0 0 0 0 0 6 (2.7)0 0 0 0 0 4 (1.8)

1 (2.4) 1 (2.6) 1 (2.6) 0 0 7 (3.1)0 1 (2.6) 0 1 (2.7) 0 6 (2.7)0 0 0 0 1 (2.4) 4 (1.8)0 2 (5.3) 0 0 1 (2.4) 5 (2.2)

1 (2.4) 1 (2.6) 1 (2.6) 1 (2.7) 1 (2.4) 6 (2.7)1 (2.4) 3 (7.9) 2 (5.3) 1 (2.7) 0 10 (4.4)

0 0 0 1 (2.7) 0 3 (1.3)0 1 (2.6) 2 (5.3) 1 (2.7) 0 5 (2.2)0 0 1 (2.6) 0 1 (2.4) 3 (1.3)0 0 1 (2.6) 0 0 3 (1.3)0 0 0 0 2 (4.9) 3 (1.3)0 0 1 (2.6) 5 (13.5) 0 7 (3.1)

1 (2.4) 0 1 (2.6) 3 (8.1) 0 5 (2.2)0 1 (2.6) 1 (2.6) 1 (2.7) 0 3 (1.3)0 1 (2.6) 0 2‡(5.4) 0 3 (1.3)

e phosphokinase; URTI � upper respiratory tract infection.

withts wi

Placebon � 15

8 (53.3

5 (33.3

3 (20.00

1 (6.7)0

1 (6.7)1 (6.7)

0000

1 (6.7)0000

1 (6.7)000

creatin

avorable tolerability profiles of other ARBs,6 for

Volume 34 Number 6

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wstecepefsihtlbst

H. Lee et al.

which dizziness and headache were the most frequentlyreported TEAEs.8,20

Concern has been raised about elevations in liverenzymes, which was most frequently reported aftertreatment with fimasartan 240 mg, the highest dosein both studies 1 and 2 combined. However, elevatedliver enzymes were also reported with the lower fi-masartan doses and with placebo, with no statisti-cally significant differences among the treatmentgroups. Follow-up of patients with elevated liver en-zymes revealed no remaining abnormalities. Furtherclinical studies should carefully investigate whetherand, if so, how severely, fimasartan increases liverenzymes, particularly at higher doses such as240 mg.

The present studies had several limitations. The pri-mary analysis population did not include imputed datafor missing outcomes, which might have resulted in theloss of the statistical power by reducing the sample size.However, the BP-lowering effect was greater with fi-masartan compared with placebo, making the lostpower less of an issue. Given that hypertension is achronic, progressive disease, the underlying assump-tions for data imputation may be invalid.33,34 More-ver, data-imputation methods such as the LOCF ap-roach may have introduced bias.35 In any case, andditional LOCF analysis was performed on data onlinic BP, the findings of which were similar to thoserom a non-LOCF analysis, adding confidence to theonclusions.

The use of DBP as the sole enrollment criterion,hich led to the exclusion of patients with isolated

ystolic hypertension, may limit the applicability ofhe findings to this patient population. The singlethnicity (Korean) of the participants may be per-eived as another limitation in the same sense. How-ver, it may be unlikely for those excluded patientopulations to have had considerable effects on thefficacy and tolerability profiles of fimasartan for theollowing reasons. First, because fimasartan was as-ociated with significant reductions in SBP and DBP,t is less probable that patients with isolated systolicypertension would respond poorly to fimasartanreatment. Similarly, in a previous study, more over-ap than separation was noted between white andlack populations in the responses to antihyperten-ive drug treatments, which makes ethnicity-based
herapy less likely.36
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CONCLUSIONSFimasartan, compared with placebo, was associatedwith significant decreases in BP in these selected Ko-rean patient populations with hypertension. Once-daily administration adequately maintained reductionsin BP throughout the dosing interval. The dose-re-sponse relationship of fimasartan was flat, with 60 mgbeing the minimum effective dose. Fimasartan was welltolerated.

ACKNOWLEDGMENTSThe authors thank Boryung Pharmaceutical Co, Ltd,Seoul, Korea, for a grant to conduct the present studies.

All authors contributed equally to the literaturesearch, data interpretation, figure creation, and writingof the manuscript.

CONFLICT OF INTERESTBoryung Pharmaceutical provided a grant to conductthe present studies; the grant covered the medical costsfor patients and the compensation for the time of studypersonnel. All study drugs were provided for free. Thesponsor was involved in the initial phase of the studydesign, and all other activities, including subject enroll-ment, study conduct, data analysis, and presentation ofthe data were carried out by the authors and/or thosewhom they delegated under their supervision. Thesponsor monitored the conduct of the present studiesbecause that was a regulatory requirement based onthe Korean Good Clinical Practice Guideline.

None of the authors or investigators were or will becompensated to present or discuss the findings from thepresent studies.

Dr. Oh has received lecture honoraria from No-vartis Pharmaceuticals Corporation and Hanmi Phar-maceutical Co, Ltd, and research grant from MerckSharp & Dohme, LG Life Sciences Ltd, and BoryungPharmaceutical. Dr. H. Lee has received consultant’sfees from Boryung Pharmaceutical. The authors haveindicated that they have no other conflicts of interestwith regard to the content of this article.

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Address correspondence to: Byung-Hee Oh, MD, PhD, Department of In-ternal Medicine, Seoul National University College of Medicine, 101 Dae-
hakro, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected]
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Efficacy and Tolerability of Once-Daily Oral Fimasartan 20 to 240 mg/d in Korean Patients with Hypertension: Findings from Two Phase II, Randomized, Double-Blind, Placebo-Controlled