Comparison of Efficacy and Safety Between Bisoprolol Transdermal Patch (TY‐0201) and Bisoprolol Fumarate Oral Formulation in Japanese Patients With Grade I or II Essential Hypertension: Randomized, Double‐Blind, Placebo‐Controlled Study

Abstract

TY‐0201 (TY) is a new drug absorbed by the transdermal delivery system developed for the treatment of hypertension, which contains the free base of bisoprolol fumarate that is widely used. An 8‐week randomized, double‐blind, placebo‐controlled study was conducted in hypertensive patients to evaluate the superiority of TY 8 mg to placebo and the noninferiority of TY 8 mg to bisoprolol fumarate oral formulation (BO) 5 mg. Changes in diastolic blood pressure (BP) (primary endpoint) from baseline in the TY 8 mg group, the BO 5 mg group, and the placebo group were −12.2 mm Hg, −11.8 mm Hg, and −3.7 mm Hg, respectively, with TY 8 mg demonstrating superiority to placebo and noninferiority to BO 5 mg. Changes from baseline for systolic BP and pulse rate produced significant reductions compared with placebo. TY is expected to serve as a new treatment approach for hypertensive patients.

Hypertension is closely related to cardiovascular morbidity and mortality. Roughly half of all hypertensive patients have been reported to have inadequately controlled blood pressure (BP),1 and it is recognized that tight BP control is necessary. According to the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2009 (JSH 2009),2 lowering of BP during a 24‐hour period, multiple drugs therapy, and improvement of adherence by patients are necessary in order to achieve BP‐lowering targets during treatment with antihypertensive drugs. In order to achieve tight BP control, combination and long‐acting antihypertensive drugs have been recently developed.

Antihypertensive drugs in the form of transdermal patches are considered to be highly clinically significant in terms of stable control of BP during a 24‐hour period by sustaining a constant plasma concentration and facilitating the application of drug therapy for hypertensive patients in a state unsuitable for oral administration, such as patients with difficulty swallowing. Therefore, bisoprolol, a β‐blocker with high skin permeability and low skin irritation, was selected as a result of conducting skin permeability screening and safety tests on several types of existing drugs (or free bases of them) considered to have high therapeutic value. Bisoprolol, the free base form of bisoprolol fumarate oral formulation (BO), is widely used in patients with hypertension, angina pectoris, and congestive heart failure; demonstrates high selectivity for β₁ receptors; and is eliminated from the body in a favorable balance via two routes through the liver and kidneys without intrinsic sympathomimetic activity.3 TY‐0201 (TY) is a new transdermal β‐blocker formulation containing bisoprolol, and TY 8 mg was designed to maintain a sustained concentration of bisoprolol in plasma by lower peak plasma bisoprolol concentration and higher trough concentration than BO 5 mg, thereby demonstrating an area under the curve for plasma concentration similar to that of BO 5 mg.

In this study, the superiority of TY 8 mg to placebo and its noninferiority to BO 5 mg by a randomized, double‐blind, placebo‐controlled comparative study for 8 weeks in Japanese patients with grade I or II essential hypertension were examined.

Methods

Study Design

This study was a phase III, multi‐institutional randomized, double‐blind, placebo‐controlled study in Japanese patients with grade I or II essential hypertension. The study was conducted at 24 institutions in Japan from August 2010 to May 2011. Patients entered a placebo run‐in period of 4 weeks, and patients who satisfied the inclusion criteria were assigned to either the TY 8 mg group (TY 8 mg patches and BO placebo tablets), the BO 5 mg group (TY placebo patches and BO 5 mg tablets), or the placebo group (TY placebo patches and BO placebo tablets) at a ratio of 2:2:1, followed by administration of drugs prepared according to the double‐dummy method once a day for 8 weeks. The patches were applied to the chest, upper back, or upper arm. The patients visited their respective institutions every 2 weeks and their BP and pulse rate (PR) were measured in the morning. In addition, ambulatory BP monitoring (ABPM) was performed once each during the placebo run‐in period and at the end of 8‐week treatment period. Patients were administered drugs between the times from waking up in the morning until 12 pm regardless of when they ate breakfast, and were administered drugs after completion of measurement of BP when they visited their respective institutions.

This study was approved by the institutional review board at each study center. In addition, the study was conducted in compliance with the Declaration of Helsinki and Guidelines for Good Clinical Practice (GCP). All patients provided written informed consent.

This study has been registered in the Clinical Trials Information of the Japan Pharmaceutical Information Center (Japic CTI) and can be viewed at http://www.clinicaltrials.jp/user/cteSearch.jsp (JapicCTI‐101257).

Participants

The participants in this study consisted of Japanese men and women with grade I or II essential hypertension ranging in age from 20 to 80 years. Inclusion criteria included sitting diastolic BP (DBP) ≥90 mm Hg and <110 mm Hg at week −2, sitting DBP ≥95 mm Hg, and <110 mm Hg at week 0, with a ≤10 mm Hg difference in sitting DBP between the two measurements, and the mean 24‐hour DBP measured by ABPM ≥80 mm Hg during placebo run‐in period. Exclusion criteria included secondary hypertension, malignant hypertension, sitting systolic BP (SBP) ≥180 mm Hg and/or DBP ≥110 mm Hg, and sitting PR <60 beats per minute at week −2 or at week 0. In addition, patients with serious heart disease, liver disease, or kidney disease as well as patients with clinically significant allergies were also excluded. Patients with bronchial asthma, a history of malignant tumor in the past 5 years, pregnant patients, patients with a history of digestive tract surgery having a detrimental effect on drug absorption, patients with poor skin condition at the patch application site, and patients who had received administration of other test drugs/investigational products within 4 months prior to participation were also excluded.

During the study, concomitant use of other antihypertensive drugs, vasodilators, nitrates, coronary vasodilators, circulatory hormones, nonsteroidal anti‐inflammatory drugs, tricyclic antidepressants, and antiarrhythmic drugs was prohibited.

Study Procedures

In the patients who had been treated with antihypertensive agents, these antihypertensive agents were withdrawn prior to the placebo run‐in period. The patients were administered TY 8 mg or BO 5 mg or placebo for 8 weeks after the placebo run‐in period for 4 weeks. The patients visited their respective institutions every 2 weeks and SBP, DBP, and PR were measured. SBP, DBP, and PR were measured 3 times at 1‐ to 2‐minute intervals in a sitting position at trough (24±2 hours post‐dose) using an automatic sphygmomanometer (TM‐2580, A&D Co, Ltd, Tokyo, Japan). It was reported that the first BP reading was relatively high compared with consecutive readings,4 thus the mean of the last two readings was used for analysis in order to obtain stable BP value.5 ABPM was performed at baseline and at week 8 using a portable automatic sphygmomanometer (TM‐2431, A&D Co, Ltd) by monitoring for 25 hours or more at 30‐minute intervals. The patients were prohibited from bathing, engaging in strenuous exercise, consuming alcohol, or driving an automobile during the ABPM monitoring period. Chest x‐rays were taken at baseline and at week 8, and a 12‐lead electrocardiogram and clinical laboratory testing were carried out at baseline, at week 4, and at week 8. Patients were discontinued from the study if their sitting SBP ≥180 mm Hg and/or DBP ≥110 mm Hg, and sitting PR <45 beats per minute when the patients visited their respective institution during the treatment period.

Study Endpoints

The primary endpoint was a change at week 8 in the office DBP from baseline, and secondary endpoints were changes at week 8 in the office SBP and PR from baseline. If the case data were missing from measurements performed at week 8, the last observation carried forward (LOCF) method was used in which missing data were supplemented by using data observed in the last measurement performed prior to the missing measurement. Other secondary endpoints included changes at week 8 in SBP, DBP, and PR measured by ABPM from baseline, and the proportion of patients responding to treatment (DBP <90 mm Hg at week 8 and/or 10 mm Hg reduction from baseline). Safety was evaluated based on the incidences of treatment‐emergent adverse events (TEAEs) and TEAEs that were considered treatment‐related.

Statistical Analysis

Noninferiority Margin

Since the difference in changes in DBP from baseline between BO 5 mg and placebo had been shown as 6.6 mm Hg by a clinical study on BO,6 the value of 3.3 mm Hg corresponding to 50% of that value was set for the noninferiority margin of TY 8 mg with respect to BO 5 mg.

Sample Size

The sample size was calculated using the change in DBP of TY 8 mg from baseline following an 8‐week treatment period in an earlier dose‐finding study of TY in Japanese patients with hypertension (unpublished data). As the study showed that the standard deviation of TY 8 mg was estimated as 9.9 mm Hg, the common standard deviation in all groups was assumed to be 10 mm Hg. When the difference between TY 8 mg and BO 5 mg was assumed to be 0.0 mm Hg and the statistical power was taken to be 80%, the number of subjects enabling confirmation of noninferiority in the TY 8 mg group as determined by t test using a one‐sided significance level of 0.025 was calculated to be at least 146 per group. In addition, the number of patients in the placebo group was set at 73, equal to half the number of the TY 8 mg group. In this case, in order to detect a difference of 6.6 mm Hg in the change in DBP from baseline between the TY 8 mg group and the placebo group, the statistical power that indicates superiority in a t test using a two‐sided significance level of 0.05 was more than 90%. Assuming a dropout rate of 10%, the total final sample size was determined to be 410 patients, consisting of 164, 164, and 82 in the TY 8 mg group, the BO 5 mg group, and the placebo group (ratio: 2:2:1).

ABPM Data

ABPM data were handled according to the predetermined procedure indicated below.7

• Data were used that were obtained over the next 24 hours after omitting data recorded during the first hour after the start of ABPM monitoring.

• Recordings were omitted if they did not satisfy any one of the following conditions:

  • 70 mm Hg ≤ ABPM SBP ≤250 mm Hg

  • 40 mm Hg ≤ ABPM DBP ≤130 mm Hg

  • 20 mm Hg ≤ pulse pressure ≤ 150 mm Hg

• When analyzing mean 24‐hour, daytime (9 _AM to 9 _PM), nighttime (0:00 _AM to 5 _AM), and morning values (each 3 hours before and after waking up), data were not used unless at least 8 hourly values were present for daytime and at least 4 hourly values were present for nighttime.

Analysis of Endpoints

Efficacy was analyzed for a full analysis set (FAS) of randomized patients, excluding GCP violation, ineligible, not administered a study drug during the treatment period and there were no efficacy data. Safety was analyzed for a safety analysis set excluding GCP violation, not administered a study drug during the treatment period and there were no safety data.

Changes in DBP at week 8 from baseline, which was used for the primary endpoint, were analyzed by calculating the adjusted mean and 95% confidence interval (CI) for each treatment group by linear model analysis using the treatment groups and baseline values as fixed effects.

First, the difference between the TY 8 mg group and the placebo group was calculated, and in the case where the upper limit of its 95% CI was <0, the superiority of TY 8 mg to placebo was demonstrated. Second, in the case where the superiority of TY 8 mg to placebo was observed, the difference between the TY 8 mg group and BO 5 mg group was evaluated, and in the case where the upper limit of its 95% CI was less than the noninferiority margin of 3.3 mm Hg, the noninferiority of TY 8 mg to BO 5 mg was demonstrated. Moreover, in the case where the noninferiority of TY 8 mg to BO 5 mg was observed, the superiority of TY 8 mg to BO 5 mg was demonstrated in the case where the upper limit of the 95% CI of the difference between the TY 8 mg group and the BO 5 mg group was <0.

Changes in SBP and PR at week 8 from baseline were analyzed by calculating the adjusted mean and 95% CI for each treatment group in the same way as that for the primary endpoint. In addition, changes in SBP, DBP, and PR measured by ABPM at week 8 from baseline (24‐hour, daytime, nighttime, morning, and hourly values) were analyzed by calculating the mean and 95% CI for each treatment group. The proportion of patients responding to treatment was calculated for each treatment group. Testing multiplicity was not taken into consideration for secondary endpoints.

When analyzing the safety evaluation, adverse events at the patch application site that appeared in the BO 5 mg group were excluded from the analysis because they were events observed following application of the placebo patch according to the double‐dummy method and do not inherently appear during oral administration of BO 5 mg.

All analyses were performed using SAS version 9.2 (SAS Institute Japan Ltd, Tokyo, Japan).

Results

Patients Characteristics

A total of 578 patients provided informed consent for participation in the study, among which 460 patients who were estimated as eligible were randomized: 184 patients in the TY 8 mg group, 183 patients in the BO 5 mg group, and 93 patients to the placebo group. One hundred seventy‐six patients in the TY 8 mg group, 172 patients in the BO 5 mg group, and 89 patients in the placebo group successfully completed the study (Figure 1). Following completion of the study, 1 patient in the BO 5 mg group was determined to not satisfy the inclusion criteria for the 24‐hour DBP measured by ABPM at baseline and was excluded from the FAS.

Figure 1.

Disposition of patients in the study. PR indicates pulse rate; SBP, systolic blood pressure; DBP, diastolic blood pressure.

There were no differences in the demographic characteristics at baseline in any of the groups (Table 1). The average age of patients in the TY 8 mg group, the BO 5 mg group, and the placebo group were 50.3 years, 50.7 years and 51.3 years, respectively, and the proportions of men in each group were 64.1%, 63.7%, and 66.7%, respectively.

Table 1.

Baseline Demographic and Clinical Characteristics of Study Patients (FAS Population)

Characteristic	TY 8 mg (n=184)	BO 5 mg (n=182)	Placebo (n=93)
Age, y	50.3±8.9	50.7±9.0	51.3±9.3
Male	118 (64.1)	116 (63.7)	62 (66.7)
Female	66 (35.9)	66 (36.3)	31 (33.3)
Height, cm	164.96±8.13	165.85±9.10	164.93±8.07
Weight, kg	70.35±14.60	69.94±12.63	70.49±12.34
BMI, kg/m2	25.69±4.05	25.32±3.44	25.87±3.84
Sitting SBP, mm Hg	150.9±9.9	151.3±9.9	148.9±8.9
Sitting DBP, mm Hg	99.9±3.9	99.9±3.8	99.5±3.8
Sitting PR, beats per min	76.3±10.2	74.7±8.5	75.4±9.7
ABPM SBP, mm Hg
24‐h	152.6±13.4	154.6±12.0	154.4±13.0
Daytime	159.0±13.3	160.9±11.9	160.1±12.6
Nighttime	140.2±17.6	141.9±15.5	143.3±18.4
Morning	148.6±15.9	150.9±14.7	149.7±15.8
ABPM DBP, mm Hg
24‐h	96.1±7.8	96.4±7.8	97.2±7.6
Daytime	100.0±7.9	100.1±7.9	101.0±7.7
Nighttime	88.0±10.2	88.5±10.0	89.8±10.4
Morning	94.5±9.1	95.2±8.5	95.0±8.7
ABPM PR, beats per min
24‐h	74.0±8.1	72.2±7.8	72.8±9.0
Daytime	79.2±9.3	77.2±9.0	77.5±9.6
Nighttime	65.3±9.0	63.6±8.1	64.7±9.1
Morning	69.4±7.9	67.8±7.7	68.7±9.3
Diabetes mellitus	11 (6.0)	8 (4.4)	8 (8.6)
Hyperlipidemia	91 (49.5)	89 (48.9)	42 (45.2)
Hyperuricemia	43 (23.4)	30 (16.5)	25 (26.9)
Previous antihypertensive treatment	86 (46.7)	85 (46.7)	46 (49.5)

Abbreviations: ABPM, ambulatory blood pressure monitoring; BMI, body mass index; BO, bisoprolol fumarate oral formulation; DBP, diastolic blood pressure; FAS, full analysis set; PR, pulse rate; SBP, systolic blood pressure; TY, TY‐0201. Values are means±standard deviation or number (percentage).

SBP, DBP, and PR Measured in the Office

First, the superiority of TY 8 mg to placebo was demonstrated for changes from baseline DBP following the 8‐week treatment period (LOCF) used as the primary endpoint. Changes in DBP from baseline in the TY 8 mg group and placebo group were −12.2 mm Hg and −3.7 mm Hg, respectively, thus indicating the superiority of TY 8 mg to placebo (TY 8 mg group – placebo group: −8.4 mm Hg, 95% CI, −10.6 to −6.2; P<.0001). Second, the noninferiority of TY 8 mg to BO 5 mg was demonstrated based on the noninferiority margin of 3.3 mm Hg. Since the change in DBP from baseline in the BO 5 mg group was −11.8 mm Hg and the upper limit value of the resulting 95% CI did not exceed the noninferiority margin of 3.3 mm Hg, the noninferiority of TY 8 mg to BO 5 mg was demonstrated (TY 8 mg group – BO 5 mg group: −0.4 mm Hg, 95% CI, −2.2 to 1.4; P=.6916). However, the superiority of TY 8 mg to BO 5 mg was not demonstrated. Changes from baseline SBP and PR following the 8‐week treatment period (LOCF) used as secondary endpoints produced significant reductions compared with placebo (Figure 2).

Figure 2.

Mean change (adjusted mean) in sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), and sitting pulse rate (PR) from baseline (week 0) to week 8 in the TY‐0201 (TY) 8 mg, bisoprolol fumarate oral formulation (BO) 5 mg, and placebo groups (full analysis set population: last observation carried forward analysis). Data are presented as mean±standard error. *Primary endpoint.

The proportions of patients responding to treatment in the TY 8 mg group, the BO 5 mg group, and the placebo group were 66.8%, 62.6%, and 26.9%, respectively, and although the response in the TY 8 mg group was significantly higher than that in the placebo group (P<.0001), there was no significant difference observed with respect to the BO 5 mg group (P=.3992).

Evaluations by ABPM

Changes in SBP, DBP, and PR from baseline (24‐hour, daytime, nighttime, and morning) and changes within a 24‐hour period in each group are shown in Table 2 and Figure 3.

Table 2.

Changes in ABPM Values From Baseline to Week 8 in TY 8 mg, BO 5 mg, and Placebo

Parameter	TY 8 mg (n=175)		BO 5 mg (n=171)		Placebo (n=88)
	Mean (SD)	95% CI	Mean (SD)	95% CI	Mean (SD)	95% CI
ABPM SBP (mm Hg)
24‐h	−8.3 (11.7)	−10.0, −6.6	−10.6 (11.8)	−12.4, −8.8	−0.5 (9.3)	−2.4, 1.5
Daytime	−8.7 (13.0)	−10.6, −6.7	−10.9 (13.8)	−13.0, −8.8	0.9 (9.8)	−1.2, 2.9
Nighttime	−8.2 (15.7)	−10.5, −5.9	−10.3 (13.8)	−12.4, −8.3	−1.9 (13.1)	−4.6, 0.9
Morning	−8.4 (14.7)	−10.6, −6.2	−10.1 (13.9)	−12.1, −8.0	−1.0 (12.7)	−3.7, 1.7
ABPM DBP (mm Hg)
24‐h	−7.8 (6.6)	−8.7, −6.8	−8.9 (7.3)	−10.0, −7.8	−0.3 (5.7)	−1.5, 0.9
Daytime	−8.1 (7.8)	−9.2, −6.9	−9.1 (8.5)	−10.3, −7.8	−0.1 (6.5)	−1.5, 1.3
Nighttime	−7.3 (8.7)	−8.6, −6.0	−8.8 (9.3)	−10.2, −7.4	−0.6 (8.2)	−2.3, 1.1
Morning	−8.1 (8.6)	−9.4, −6.8	−9.2 (8.7)	−10.5, −7.8	0.7 (7.7)	−1.0, 2.3
ABPM PR (beats per min)
24‐h	−10.6 (6.2)	−11.5, −9.6	−9.5 (5.6)	−10.3, −8.6	2.6 (5.0)	1.6, 3.7
Daytime	−12.5 (8.1)	−13.7, −11.3	−11.8 (6.9)	−12.8, −10.7	3.1 (6.1)	1.8, 4.4
Nighttime	−7.3 (6.6)	−8.3, −6.3	−6.0 (6.4)	−7.0, −5.0	2.0 (6.4)	0.7, 3.4
Morning	−9.2a (6.5)	−10.1, −8.2	−7.2 (5.8)	−8.1, −6.4	2.5 (6.7)	1.0, 3.9

Abbreviations: ABPM, ambulatory blood pressure monitoring; BO, bisoprolol fumarate oral formulation; CI, confidence interval; DBP, diastolic blood pressure; PR, pulse rate; SBP, systolic blood pressure; SD, standard deviation; TY, TY‐0201. ^a P<.01 vs BO 5 mg.

Figure 3.

Average (±standard deviation) hourly systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate (PR) values at baseline (SBP: open circle, DBP: open square, PR: open circle) and at week 8 (SBP: solid circle, DBP: solid square, PR: solid circle) with TY‐0201 (TY) 8 mg, bisoprolol fumarate oral formulation (BO) 5 mg, and placebo.

Significant reductions were observed during each time period for changes in SBP, DBP, and PR from baseline in the TY 8 mg group and the BO 5 mg group. Although there were no significant differences observed in changes in SBP and DBP from baseline in the TY 8 mg group as compared with the BO 5 mg group in each time period, a significant reduction was observed for the morning only with respect to the change in PR from baseline (TY 8 mg group – BO 5 mg group: −1.9 beats per minute, 95% CI, −3.2 to −0.7; P=.0033).

Safety and Tolerability

TEAEs were observed in 75.5% of patients in the TY 8 mg group (139 of 184 patients), in 74.9% of patients in the BO 5 mg group (137 of 183 patients), and in 71.0% of patients in the placebo group (66 of 93 patients), and there were no differences observed among the groups. TEAEs ≥2% in each of the groups are shown in Table 3. There were no deaths or serious adverse events observed during the course of the study. Those patients for which the study was discontinued due to adverse events accounted for 1.6% in the TY 8 mg group (3 patients: bradycardia (discontinuance criterion: PR <45 beats per minute), dizziness, and application site dermatitis), 1.6% in the BO 5 mg group (3 patients: elevated BP, headache and nausea in the same patient, dizziness, and bradycardia), and 0% in the placebo group.

Table 3.

Treatment‐Emergent Adverse Events Occurring in TY 8 mg, BO 5 mg, and Placebo (Safety Analysis Sets)

Adverse Event	TY 8 mg (n=184), No. (%)	BO 5 mg (n=183), No. (%)	Placebo (n=93), No. (%)
Patients with ≥1 TEAE	139 (75.5)	137 (74.9)a	66 (71.0)
Patients with ≥1 TEAE considered treatment relatedb	45 (24.5)	23 (12.6)a	15 (16.1)
TEAEs leading to drug discontinuation	3 (1.6)	3 (1.6)	0 (0.0)
Serious TEAEs	0 (0.0)	0 (0.0)	0 (0.0)
Clinical TEAEsc
Nasopharyngitis	22 (12.0)	30 (16.4)	9 (9.7)
Application site pruritus	9 (4.9)	6 (3.3)	4 (4.3)
Application site dermatitis	6 (3.3)	2 (1.1)	2 (2.2)
Pharyngitis	6 (3.3)	5 (2.7)	0 (0.0)
Upper respiratory tract inflammation	2 (1.1)	2 (1.1)	2 (2.2)
Headache	2 (1.1)	1 (0.5)	2 (2.2)
Dizziness	2 (1.1)	1 (0.5)	2 (2.2)
Constipation	0 (0.0)	1 (0.5)	3 (3.2)
Laboratory TEAEsc
White blood cell count increased	6 (3.3)	7 (3.8)	2 (2.2)
Eosinophil percentage increased	12 (6.5)	11 (6.0)	7 (7.5)
Neutrophil percentage increased	1 (0.5)	4 (2.2)	1 (1.1)
Monocyte percentage increased	8 (4.3)	8 (4.4)	1 (1.1)
Basophil percentage increased	1 (0.5)	3 (1.6)	2 (2.2)
Lymphocyte percentage decreased	5 (2.7)	7 (3.8)	4 (4.3)
Alanine aminotransferase increased	5 (2.7)	7 (3.8)	2 (2.2)
Aspartate aminotransferase increased	5 (2.7)	7 (3.8)	2 (2.2)
Blood bilirubin increased	1 (0.5)	4 (2.2)	0 (0.0)
Blood creatine phosphokinase increased	9 (4.9)	21 (11.5)	11 (11.8)
Blood lactate dehydrogenase increased	4 (2.2)	6 (3.3)	0 (0.0)
Blood uric acid increased	6 (3.3)	9 (4.9)	0 (0.0)
Blood glucose increased	9 (4.9)	7 (3.8)	3 (3.2)
Blood cholesterol increased	5 (2.7)	6 (3.3)	4 (4.3)
Blood cholesterol decreased	4 (2.2)	3 (1.6)	0 (0.0)
High‐density lipoprotein decreased	8 (4.3)	6 (3.3)	1 (1.1)
Low‐density lipoprotein increased	10 (5.4)	9 (4.9)	4 (4.3)
Low‐density lipoprotein decreased	2 (1.1)	5 (2.7)	2 (2.2)
Blood triglycerides increased	49 (26.6)	41 (22.4)	18 (19.4)
Blood triglycerides decreased	7 (3.8)	3 (1.6)	2 (2.2)
Blood phosphorus decreased	3 (1.6)	5 (2.7)	2 (2.2)
C‐reactive protein increased	27 (14.7)	19 (10.4)	11 (11.8)
Glucose urine	2 (1.1)	5 (2.7)	1 (1.1)
Protein urine	8 (4.3)	8 (4.4)	9 (9.7)

Abbreviation: BO, bisoprolol fumarate oral formulation; TEAE, treatment‐emergent adverse event; TY, TY‐0201. ^aNumbers (percentages) exclude the adverse events of the application site. ^bAdverse events for which involvement of the study medications were suspected by the investigator. ^cOccurring in ≥2% of patients in either treatment group.

TEAEs considered treatment‐related were observed in 24.5% of patients in the TY 8 mg group (45 of 184 patients), in 12.6% of patients in the BO 5 mg group (23 of 183 patients), and in 16.1% of patients in the placebo group (15 of 93 patients). Adverse events at the application site in the TY 8 mg group were observed in 9.2% of patients (17 of 184 patients). All of the adverse events were mild, and application site pruritus was observed most frequently, in 4.9% of patients (9 of 184 patients). The most commonly reported TEAE in clinical laboratory values was elevation in blood triglycerides, and although this was observed in 3.8% of patients in the TY 8 mg group (7 of 184 patients), in 3.3% of patients in the BO 5 mg group (6 of 183 patients), and in 1.1% of patients in the placebo group (1 of 93 patients), there were no clinically significant fluctuations observed following the 8‐week treatment period compared with with the run‐in period in any of the groups. Patients in whom bradycardia was observed accounted for 1.6% in the TY 8 mg group (3 patients), 0.5% in the BO 5 mg group (1 patient), and 0% in the placebo group. There were no other significant changes observed that were considered to present a problem in clinical laboratory values, body weight, or cardiothoracic ratio. Based on the above findings, although the frequency of TEAEs considered treatment‐related in the TY 8 mg group was higher than that in the BO 5 mg group, the difference was mainly attributable to mild adverse events at the application site, and other TEAEs resembled those of the BO 5 mg group.

Discussion

This study was conducted for the purpose of demonstrating the superiority of TY 8 mg to placebo and the noninferiority of TY 8 mg to BO 5 mg by a randomized, double‐blind, placebo‐controlled design for 8 weeks in Japanese patients with grade I or II essential hypertension. The change in office DBP from baseline was used for the primary endpoint, while changes in office SBP and PR from baseline and changes in DBP, SBP, and PR measured by ABPM were also evaluated.

In this study, TY 8 mg demonstrated superiority to placebo and noninferiority to BO 5 mg with respect to changes in DBP from baseline. In addition, changes from baseline for SBP and PR produced significant reductions compared with placebo.

According to the results of ABPM, both TY 8 mg and BO 5 mg demonstrated stable BP‐lowering effects and PR‐reducing effects during a 24‐hour period. Although the 24‐hour profiles of BP and PR for TY 8 mg and BO 5 mg were similar, morning PR decreased significantly in the TY 8 mg group as compared with the BO 5 mg group. In the future, a detailed examination should be conducted on the effects of TY on 24‐hour profiles of BP and PR based on differences in the type of nighttime BP variations (such as dipper or nondipper type) or differences in background factors (such as age and sex).

The safety profiles of the TY 8 mg group and the BO 5 mg group were similar with respect to adverse events, with the exception of adverse events at the application site, and TY 8 mg is considered to have a higher incidence of adverse events compared with BO 5 mg only because of adverse events at the application site. Although 1 patient withdrew from the study because of application site dermatitis in the TY 8 mg group, and since adverse events at the application site in other patients were all mild, they were considered to be clinically acceptable. Bradycardia is an adverse event that is associated with β‐blockers. Bradycardia was observed in 3 patients in the TY 8 mg group and 1 patient in the BO 5 mg group in this study; thus, the greatest care is necessary in the clinical use of these agents. Furthermore, since the PR of baseline values in those patients in whom bradycardia occurred were all at the level of 60 beats per minute, caution is particularly required with respect to bradycardia when administering these drugs to patients with a low PR.

TY is a new transdermal β‐blocker formulation that contains bisoprolol as an active ingredient. TY can be used in essential hypertensive patients in a condition that makes them unsuitable for oral administration (such as patients with difficulty swallowing or patients exhibiting poor absorption from the intestines due to diseases affecting the digestive tract) as well as ordinary hypertensive patients. Dysphagia is frequently observed in patients exhibiting cerebral infarction sequelae.8 In addition, there are many cases in which patients with cerebral infarction sequelae are also complicated with hypertension, and since such patients exhibit a high rate of recurrence due to inadequate BP control,9, 10 TY is considered to provide a new strategy of treatment that facilitates BP management. In addition, hypertension is also observed at a high frequency as a postsurgical complication in surgical patients. JSH 2009 and American College of Cardiology/American Heart Association 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery recommend that BP should be promptly lowered by oral administration or intravenous administration in postsurgical hypertension.2, 11 If antihypertensive oral formulation drugs cannot be administered following surgery in patients, an intravenous administration is performed. From this viewpoint as well, TY is considered to provide a new means of treatment as an alternative to transvenous administration under circumstances in which oral administration is not possible.

Moreover, since TY has superior visibility because of its transdermal formulation, in addition to reducing the risk in patients who forget to medicate and facilitating medication management by a third person, it also has the potential to reduce the risk of overdose and can be expected to contribute to improved adherence. In order to utilize this benefit effectively, it is important to take steps such as recording the applied times and dates of transdermal formulations as well as providing suitable information to patients in order to promote awareness among patients to act aggressively toward treatment.12 Being able to minimize the risks associated with this transdermal patch and take full advantage of its merits is expected to contribute to the treatment of hypertension.

Conclusions

TY 8 mg demonstrated superiority to placebo as well as noninferiority to BO 5 mg in Japanese patients with grade I or II essential hypertension. Moreover, it also demonstrated superior BP‐lowering effects and tolerability during a 24‐hour period. Based on these findings, TY offers a new choice in the treatment of hypertension via a transdermal patch.

Investigators

Koichi Fujii, Otofuke Komeikan Hospital; Hideya Mera, Kyoritsu Hospital; Tamayuki Koizumi, Ishikari Hospital; Yasuhiro Saito, Kotoni Medical Support Clinic; Yuko Morita, Maruyama Lila Clinic; Hiroto Nishizawa, Odayaka Life Internal Medical Clinic; Masanori Shitaya, Shinozaki Ekimae Clinic; Kazuo Suzuki, Kenkokan Suzuki Clinic; Chiaki Noguchi, Shinkoiwa Ekimae Genaral Clinic; Otoya Miho, Miho Clinic; Hiromi Kurosawa, Yoshihiro Okada, Sakakibara Sapia Tower Clinic; Akira Numata, Ikebukuro Metropolitan Clinic; Masafumi Sugawara, Dynamedical Nezu Clinic; Munechika Noguchi, Shinagawa East One Medical Clinic; Hideki Kaizuka, Pedi Shiodome Clinic; Hiroshi Shimomura, Musashino Clinic; Kimihiko Yukisada, Yukisada Internal Medicine; Yoji Takatsuka, Motomachi Takatsuka Naika Clinic; Hitoshi Hayashi, Hayashi Katagihara Clinic; Hiroyuki Ameno, Ameno Clinic; Masahiko Kondo, Kondo Clinic; Kiyoshi Yasui, Yotsubashi Clinic; Hiroshi Tani, Tani Clinic; Ryuji Yoshimura, Yoshimura Internal Medicine.

J Clin Hypertens (Greenwich). 2013;15:806–814.