Research Report

Journal of International Medical Research

2014, Vol. 42(1) 5266
A randomized, double-blind ! The Author(s) 2014
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DOI: 10.1177/0300060513503756
and safety of a single-pill imr.sagepub.com

combination of telmisartan
80 mg/amlodipine 5 mg
versus amlodipine 5 mg in
hypertensive Asian patients
Dingliang Zhu1, Pingjin Gao1,
Werner Holtbruegge2 and Chenglei Huang3

Abstract
Objective: To investigate the efficacy and safety of telmisartan 80 mg/amlodipine 5 mg (T80/A5)
single-pill combination versus A5 in patients with essential hypertension not adequately controlled
on A5 monotherapy.
Methods: Asian patients 18 years old, with inadequately controlled blood pressure (BP) at
enrolment, who failed to achieve a seated diastolic BP (DBP) goal (90 mmHg) following 6-weeks
open-label A5 treatment, were randomly allocated 1 : 1 to 8 weeks double-blind treatment with
T80/A5 single-pill combination or A5.
Results: A total of 324 patients entered the double-blind treatment phase. The adjusted
mean  SE reduction in seated trough DBP from baseline to week 8 was significantly greater with
T80/A5 (12.4  1.0 mmHg) than A5 (10.2  0.9 mmHg [primary endpoint, n 314]). Results were
similar in the subset of 262 Chinese patients. Treatment-related adverse events were 1.9% with
T80/A5 and 2.4% with A5.
Conclusions: In Asian patients with hypertension, T80/A5 single-pill combination provided
improved BP reduction after 8 weeks treatment compared with A5 monotherapy. Both
treatments were well tolerated.

This study is registered at ClinicalTrials.gov (NCT

01103960).
1
Ruijin Hospital, Shanghai Jiaotong University School of Corresponding author:
Medicine, Shanghai, China Professor Dingliang Zhu, Shanghai Institute of
2
STATIS GmbH, Mannheim, Germany Hypertension, No. 197, Ruijin 2nd Road, Shanghai 200025,
3
Boehringer Ingelheim International Trading (Shanghai) China.
Co., Ltd, Shanghai, China Email: zhudingliang@sibs.ac.cn

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Zhu et al.
Keywords
Amlodipine, Asian, Chinese, essential hypertension, reninangiotensin system inhibitor, single-pill
combination, telmisartan, randomized controlled trial
Date received: 22 May 2013; accepted: 6 July 2013
Introduction
In the Asia Pacic region, the prevalence of
hypertension ranges between 5% and 47%
in men and between 7% and 38% in women.
Up to 66% of some subtypes of cardiovas-
cular (CV) disease such as fatal ischemic
heart disease, hemorrhagic stroke and
ischaemic stroke in this region are attributed
to hypertension.1 In China, despite a rapid
increase in the prevalence of hypertension,
only 24% of those with hypertension were
reported to be aware of their condition in a
2002 survey.2 In a multicentre, cross-sec-
tional registration survey in China, it was
observed that 30.6% of hypertensive
patients overall achieved their blood pres-
sure (BP) goal but the proportion was
<15% in those with diabetes and renal
dysfunction.3 Hence, the introduction of
formal BP-lowering strategies may have an
immense impact in the Asian region.46
Data from clinical trials suggest that
>75% of patients with hypertension require
combination therapy to achieve early BP
goals.7 Guidelines recommend the use of
xed-dose combinations to simplify treat-
ment and to improve convenience and
cost-eectiveness compared with other
therapeutic options.8 The additional BP
reduction observed by combining drugs
from two dierent classes is approximately
ve times greater than doubling the dose of
one drug,9 without an additive increase on
the incidence of adverse events (AEs).10
A single-pill combination of drugs with
complementary action has been reported to
reduce medication non-compliance by 24
26%.11 Single-pill combinations help reduce
pill burden, simplify treatment regimens and
improve treatment adherence, thereby
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53
resulting in better BP control and long-
term CV risk reduction compared with other
therapeutic options.12,13 Use of an antihy-
pertensive single-pill combination early in
the treatment paradigm (including as rst-
line medication) may help to shrink the
current gap between antihypertensive treat-
ment use and BP goal achieved, and oer
better therapeutic compliance.14
Guidelines recommend a reninangioten-
sin system inhibitor plus a calcium channel
blocker as a rational combination due
to their complementary mechanisms of
action.8,15 A single-pill combination of an
angiotensin II type 1 receptor blocker
(ARB) plus a calcium channel blocker is
emerging as perhaps the most suitable ther-
apy for preventing CV disease, in addition to
BP reduction, in patients with hyperten-
sion.16 In China, a multicentre, cross-sec-
tional registration survey of 5 086 patients
with hypertension showed calcium chan-
nel blockers (56.6%) followed by ARBs
(32.0%) to be the most commonly pre-
scribed antihypertensive medications;
>50% of patients were taking at least three
antihypertensive drugs and single-pill com-
binations were prescribed as initial therapy
in 12.7% of patients.3
Telmisartan provides superior and con-
sistent BP reductions over 24 h and beyond
compared with other ARBs.17 It is the rst
drug in the ARB class with a demonstrated
CV risk reduction, similar to ramipril, in
patients at high CV risk.18 Telmisartan is the
only ARB approved for the reduction of CV
morbidity in patients with manifest athero-
thrombotic CV disease (history of coronary
heart disease, stroke or peripheral artery
disease) or diabetes mellitus with docu-
mented target organ damage.19 The ecacy
54
and favourable safety prole of telmisartan/
amlodipine single-pill combination in
patients with hypertension has been shown
in previous multinational studies.2024
The objective of the present study was
to evaluate the ecacy and safety of the
single-pill combination of telmisartan
80 mg (T80) plus amlodipine 5 mg (A5) in
Asian patients with hypertension whose BP
was not adequately controlled on A5
monotherapy.
Patients and methods
Patients
Asian men and women, aged 18 years, with
essential hypertension and BP not ade-
quately controlled (dened as seated
diastolic BP [DBP] 95 mmHg if on anti-
hypertensive treatment, or 100 mmHg if
treatment nave) were eligible for enrolment
into the monotherapy screening phase of
the trial.
Patients with secondary hypertension,
any signicant or unstable systemic disease,
previous experience of symptoms charac-
teristic of angioedema during treatment
with angiotensin-converting enzyme inhibi-
tors or ARBs, and women who were preg-
nant, breast-feeding or planning to become
pregnant were excluded. In addition, mean
seated systolic BP (SBP) 200 mmHg and/
or mean seated DBP 120 mmHg at screen-
ing or during the run-in period, or mean
seated SBP 180 mmHg and/or mean
seated DBP 120 mmHg at the end of the
run-in period, and non-compliance with
study medication (dened as <80% or
>120%) during the run-in period were
excluded.
The study was carried out in compli-
ance with the protocol, the principles laid
down in the Declaration of Helsinki, the
International Conference on Harmonization
(ICH) Harmonized Tripartite Guidelines for
Good Clinical Practice and applicable regu-
latory requirements. The study protocol was
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Journal of International Medical Research 42(1)
reviewed by an independent ethics commit-
tee or institutional review board at each
study site, and all patients provided written
informed consent before entering the study.
Study design
This phase III, randomized, double-blind,
double dummy, multinational, multicentre
study was conducted between 28 July 2010
and 27 August 2011 at 16 investigative
sites: 12 sites in China, two sites in
Malaysia and two sites in the Philippines.
The study consisted of a 6-week open-label
monotherapy run-in period followed by an
8-week double-blind treatment period
(Figure 1). Enrolled patients were to stop
their other treatments for hypertension, if
any, before entering the run-in period.
During the 6-week run-in period, patients
received A5 once daily. Patients who
responded to the initial monotherapy were
withdrawn from the trial as screening fail-
ures. Those who did not reach the BP goal
with A5 (dened as seated trough DBP
90 mmHg after 6 weeks), were randomly
allocated in a 1 : 1 ratio to double-blind
treatment with either T80/A5 or A5 (and
placebo matching the alternative treat-
ments) once daily for 8 weeks. Treatment
allocation was determined according to the
randomization code and each eligible
patient was randomized by assigning the
lowest treatment kit number available at
the site to the patient. A complete block of
randomization numbers was assigned to
each centre.
The T80/A5 treatment was provided as
single-pill combination tablets; A5 was
provided as over-encapsulated capsules con-
taining A5 tablets. Investigators counted the
tablets for each patient at each visit post-
randomization, and percentage medication
compliance was calculated as the number of
tablets actually taken since last count/
number of tablets that should have been
taken in the same period 100.
Zhu et al. 55

Figure 1. Study design and patient flow diagram for patients enrolled into a randomized, double-blind study
to evaluate the efficacy of a single-pill combination of telmisartan 80 mg plus amlodipine 5 mg compared with
amlodipine 5 mg monotherapy. *Five patients in each treatment group were not included in the full analysis set,
due to lack of primary endpoint information. Patients visited the study centre for efficacy and safety
assessments after 4 weeks and 8 weeks during the double-blind treatment period. Baseline data for clinical
characteristics and demographics were obtained at screening. For efficacy endpoints, the baseline value was
the pre-dose measurement taken at randomization.

Efficacy assessments screening visit, BP was measured in both

Seated BP was measured at each visit using a
standard validated and calibrated trad-
itional manual cu sphygmomanometer. A
random zero sphygmomanometer with
blinded measurements or automated device
were not permitted. BP measurements were
performed on the same arm and, if possible,
by the same person at all study visits. At the
arms. If the pressures diered by
>10 mmHg, simultaneous readings were
obtained in both arms, and the arm with
the higher BP was used for subsequent
measurements. The accuracy of BP meas-
urements was increased by taking the mean
of three consecutive measurements about
2 min apart.

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56
Primary endpoint. The primary endpoint was
the change from baseline of the mean seated
trough DBP in: (a) the complete set of all
randomized patients with hypertension who
failed to respond adequately to treatment
with A5 monotherapy; and (b) in the subset
of Chinese patients who failed to respond
adequately to treatment with A5
monotherapy.
Secondary endpoints. The key secondary end-
point was the change from baseline in seated
trough SBP. Other secondary endpoints
included: the proportion of patients achiev-
ing the BP goal (mean seated trough BP
<140/90 mmHg); DBP goal attainment
(mean seated trough DBP <90 mmHg);
SBP goal attainment (mean seated trough
SBP <140 mmHg); the proportion of
patients achieving DBP response (mean
seated trough BP <90 mmHg or DBP reduc-
tion 10 mmHg); the proportion of patients
achieving SBP response (mean seated trough
SBP <140 mmHg or SBP reduction
15 mmHg); the proportion of patients
with optimal BP (<120/80 mmHg); the pro-
portion of patients with normal BP (<130/
85 mmHg and not optimal); the proportion
of patients with high-normal BP (<140/
90 mmHg and not optimal or normal); the
proportion of patients with grade 1 (mild)
hypertension, <160/<100 mmHg, but not
high-normal; grade 2 hypertension (moder-
ate), <180/<110 mmHg, but not grade 1
hypertension; grade 3 hypertension (severe):
180/110 mmHg.
Ecacy endpoints were assessed after 4
and 8 weeks treatment after the 6-week run-
in period or at last trough observation
during the double-blind treatment period.
Safety assessments
Standard physical examinations, laboratory
tests and 12-lead electrocardiogram assess-
ments were carried out at screening, at
randomization, and at the end of the study
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Journal of International Medical Research 42(1)
or at early withdrawal. Pulse rate and AEs
were recorded at all visits.
Statistical analyses
To demonstrate the superiority of T80/A5
over A5 in the reduction from baseline in
seated trough DBP of 3.5 mmHg, with a
common standard variation of 8 mmHg
(two-sided, a 0.05) at about 96% power,
152 evaluable patients per treatment group
(n 304 in total) were needed. Assuming a
5% early withdrawal rate, a total of 320
patients were needed for a 1 : 1 randomiza-
tion to the two treatment groups. Using the
same assumptions, there was about 92%
power to demonstrate the superiority of
T80/A5 over A5 in the subset of 260
Chinese patients to be randomized.
For continuous variables, data were
summarized using descriptive statistics.
Treatment comparisons were performed
using Students t-test for independent sam-
ples. For categorical variables, data were
summarized using frequency counts and
percentages. Treatment comparisons were
performed using 2-test or Fishers exact
test, if appropriate. The primary and key
secondary ecacy endpoints were com-
pared between treatment groups using an
analysis of covariance model including
treatment, country and predose random-
ization baseline measurement as covariates.
Other secondary ecacy endpoints were
compared between treatment groups using
Fishers exact test. Safety endpoints were
summarized. Last observation carried for-
ward was used to impute missing data for
the endpoints involving seated trough BP
measurements (last trough observation
carried forward). The remaining ecacy
variables and all safety variables were
analysed without substitution of missing
values.
The run-in set included all patients who
were treated during the run-in period. The
full analysis set, which included all patients
Zhu et al.
who took at least one dose of double-blind
trial medication, and for whom a baseline
measurement and at least one post-baseline
trough ecacy measurement were available,
was used for ecacy analysis. The treated
set, which included all randomized patients
who were dispensed double-blind study
medication and who took at least one dose
of investigational treatment, was used for
safety analysis. All tests were conducted as
two-tailed at the 5% level of signicance.
P-values from the treatment comparisons
0.05 were considered statistically signi-
cant. SAS software, version 9.2 (SAS
Institute Inc., Cary, NC, USA) was used
for all analyses.
Results
Patients
A total of 405 patients were enrolled in the
study: 381 entered the run-in period, 324
were randomized to double-blind treatment
and 317 completed the treatment period
(Figure 1). Fifty-seven patients from the
run-in period were not randomized to
double-blind treatment because they did
not meet the entry criteria (i.e. DBP was
<90 mmHg). The most frequent reasons for
study discontinuation during the rando-
mized treatment period were AEs and
patient refusal to continue trial medication,
each of which was reported in two patients
in the A5 group and one patient in the
T80/A5 group.
Demographic and baseline characteristics
of the patients (obtained at screening) were
similar in the two treatment groups (no
between-group statistical analyses were per-
formed on these data; Table 1). Most
patients 276/314 (87%) had received pre-
vious antihypertensive therapy. Mean SBP/
DBP was >150/>100 mmHg in the two
treatment groups; none of the patients had
DBP <90 mmHg, and less than a quarter of
patients in each of the treatment groups had
SBP <140 mmHg. Most patients were
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57
nonsmokers and did not consume alcohol.
At baseline, >60% of patients in the A5 and
T80/A5 groups had grade 1 hypertension
(Table 2).
Mean BP values at screening, the start of
run-in, and randomization were balanced
between the two treatment groups. At ran-
domization, mean  SE SBP was 146.27 
0.88 mmHg in the A5 group and 146.44 
0.98 mmHg in the T80/A5 group, and
mean  SE DBP was 97.84  0.51 mmHg in
the A5 group and 97.21  0.44 mmHg in the
T80/A5 group. Percentage medication com-
pliance was 92.7% during the run-in period,
and >99% during the randomized treatment
period. During the run-in period, mean 
SD exposure was 43.77  2.67 days. During
the randomized period, for the treated set,
the mean  SD exposure was similar in the
A5 group (58.93  8.57 days; range 475
days) and in the T80/A5 group (59.66  5.86
days; range 1672 days; no between-group
statistical analyses were performed on the
exposure data).
The demographic and baseline charac-
teristics of Chinese patients were consist-
ent with those of the overall population
and were similar in the two treatment
groups. The demographic and baseline
characteristics (obtained at screening) of
the full analysis set were similar to those
of the treated set and run-in set (data not
shown).
Efficacy
Primary endpoint. Adjusted mean  SE reduc-
tion in seated trough DBP from baseline to
week 8 in the full analysis set was signi-
cantly greater in the T80/A5 group (12.4 
0.95 mmHg) than in the A5 group (10.2 
0.93 mmHg; P 0.007; Figure 2A). Similar
results were observed in the subset of
Chinese patients (mean  SE reduction in
seated trough DBP: T80/A5 group,
10.77  0.64 mmHg; A5 group, 8.85 
0.63 mmHg; P 0.034; Figure 2B).
58 Journal of International Medical Research 42(1)

Table 1. Demographic and baseline characteristics of the full analysis set of Asian patients enrolled in a
randomized, double-blind study to evaluate the efficacy of a single-pill combination of telmisartan 80 mg plus
amlodipine 5 mg (T80/A5) compared with amlodipine 5 mg monotherapy (A5).

Treatment group

Characteristic A5 n 159 T80/A5 n 155 Total n 314

Age, years 52.4  9.7 52.4  8.7 52.4  9.2

Age group, years
<65 141 (88.7) 141 (91.0) 282 (89.8)
65 18 (11.3) 14 (9.0) 32 (10.2)
Sex
Female 71 (44.7) 78 (50.3) 149 (47.5)
Male 88 (55.3) 77 (49.7) 165 (52.5)
BMI, kg/m2 26.4  3.9 26.1  3.1 26.3  3.5
Pulse rate, beats per min 71.8  7.9 70.7  7.6 71.3  7.8
Duration of hypertension, years 8.4  8.46 7.7  8.90 8.0  8.67
Duration of hypertension, years
<1 19 (11.9) 27 (17.4) 46 (14.6)
15 62 (39.0) 64 (41.9) 127 (40.4)
610 32 (20.1) 22 (14.2) 54 (17.2)
>10 46 (28.9) 41 (26.5) 87 (27.7)
Previous antihypertensive therapy
Nave 20 (12.6) 18 (11.6) 38 (12.1)
Treated 139 (87.4) 137 (88.4) 276 (87.9)
SBP, mmHg 155.75  0.97 155.75  1.08 155.75  0.72
DBP, mmHg 103.27  0.45 103.32  0.49 103.30  0.33
SBP control 38 (23.9) 37 (23.9) 75 (23.9)
DBP control 0 0 0
Smoking status
Never smoked 110 (69.2) 108 (69.7) 218 (69.4)
Ex-smoker 5 (3.1) 8 (5.2) 13 (4.1)
Current smoker 44 (27.7) 39 (25.2) 83 (26.4)
Alcohol status
Does not drink any alcohol 113 (71.1) 108 (69.7) 221 (70.4)
Drinks alcohol, no interference 46 (28.9) 46 (29.7) 92 (29.3)
Drinks alcohol, possible interference 0 (0.0) 1 (0.6) 1 (0.3)
Chinese patients 133 (83.6) 129 (83.2) 262 (83.4)

Data presented as mean  SD, n (%), or mean  SE (systolic blood pressure [SBP] and diastolic blood pressure [DBP] only).
BMI, body mass index.

Secondary endpoints. Adjusted mean  SE 8 in seated SBP was signicantly greater in

reduction from baseline to week 8 in seated
SBP (key secondary endpoint) was signi-
cantly greater in the T80/A5 group
(16.15  1.33 mmHg) than in the A5
group (11.66  1.30 mmHg; P < 0.001).
Similarly, in the subset of Chinese patients,
mean  SE reduction from baseline to week
the T80/A5 group (13.69  0.88 mmHg)
than in the A5 group (9.38  0.87 mmHg;
P < 0.001).
The BP goal attainment rate (<140/
<90 mmHg) at week 8 was signicantly
higher in the T80/A5 group (64.5%; 95%
condence interval [CI] 56.4, 72.0) than in

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Zhu et al. 59

Table 2. Blood pressure (BP) response categories by visit of the full analysis set of patients enrolled in a
randomized, double-blind study to evaluate the efficacy of a single-pill combination of telmisartan 80 mg plus
amlodipine 5 mg (T80/A5) compared with amlodipine 5 mg monotherapy (A5).

Treatment group

A5 T80/A5

Baseline Week 4 Week 8 Baseline Week 4 Week 8

Characteristic n 159 n 159 n 159 n 155 n 155 n 155

BP response categorya
BP optimal 0 (0.0) 1 (0.6) 7 (4.4) 0 (0.0) 7 (4.5) 11 (7.1)
BP normal 0 (0.0) 20 (12.6) 33 (20.8) 0 (0.0) 26 (16.8) 36 (23.2)
BP high-normal 0 (0.0) 35 (22.0) 32 (20.1) 0 (0.0) 44 (28.4) 53 (34.2)
Grade 1 hypertension 100 (62.9) 81 (50.9) 69 (43.4) 94 (60.6) 62 (40.0) 48 (31.0)
Grade 2 hypertension 48 (30.2) 17 (10.7) 15 (9.4) 57 (36.8) 15 (9.7) 5 (3.2)
Grade 3 hypertension 11 (6.9) 5 (3.1) 3 (1.9) 4 (2.6) 1 (0.6) 2 (1.3)

Data presented as n (%) of patients.

a
T80/A5 versus A5 for shift towards better response categories: after 4 weeks randomized treatment, P 0.0411; after 8
weeks randomized treatment, P 0.0078; Fishers exact test. Individual categories were not compared between treatment
groups.
BP optimal, <120/80 mmHg; BP normal, <130/85 mmHg; BP high-normal, <140/90 mmHg; Grade 1 hypertension (mild),
<160/<100 mmHg; Grade 2 hypertension (moderate), <180/<110 mmHg; Grade 3 hypertension (severe), 180/
110 mmHg.

the A5 group (45.3%; 95% CI 37.4, 53.4;
P 0.0007). The percentage of patients
achieving the seated trough DBP
goal (<90 mmHg) and seated trough SBP
goal (<140 mmHg) at week 8 was also
signicantly higher in the T80/A5 group
than in the A5 group (Figure 3). The response
rates for DBP (<90 mmHg and/or reduction
from baseline 10 mmHg) and SBP
(<140 mmHg and/or reduction from base-
line 15 mmHg) were signicantly higher in
the T80/A5 group compared with the A5
group at both week 4 and week 8 (Figure 4).
The percentage of patients whose BP was
normalized was higher for each response
category (optimal, normal or high-normal)
in the T80/A5 group than in the A5 group at
week 4 and week 8 (Table 2). The percent-
ages of patients with grade 1, 2 or 3 hyper-
tension decreased from baseline in both
treatment groups at week 4 and week 8,
with larger decreases from baseline in the
percentage of patients with grade 1 and
grade 2 hypertension in the T80/A5 group
than the A5 group (Table 2).
Safety. During the run-in period, 26 of the
381 patients (6.8%) experienced an AE. The
most frequently reported (those occurring in
more than one patient) AEs were dizziness
(n 9, 2.4%), headache (n 7, 1.8%) and
cough (n 2, 0.5%). One patient died
(sudden death) and one patient experienced
a serious AE of cerebrovascular accident.
Both were considered by an independent
physician to be not related to study treat-
ment. Treatment-related AEs occurred in 12
patients (3.1%): the most common (occur-
ring in more than one patient) were head-
aches (n 7, 1.8%) and dizziness (n 5,
1.3%). Six patients (1.6%) discontinued
due to AEs: dizziness was the most
common reason (occurring in more than
one patient) (n 4, 1%).

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60
Figure 2. Adjusted mean reductions from base-
line to week 8 in seated trough diastolic blood
pressure (DBP) in (A) 314 Asian patients and (B) a
subset of 262 Chinese patients, enrolled in a
randomized, double-blind study to evaluate the
efficacy of a single-pill combination telmisartan
80 mg plus amlodipine 5 mg (T80/A5) compared
with amlodipine 5 mg monotherapy (A5). Treatment
groups were compared using an analysis of covari-
ance model including treatment, country and
pre-dose randomization baseline measurement as
covariates; P  0.05.
During the randomized treatment period,
similar percentages of patients in the two
treatment groups reported AEs. The most
frequently reported AEs (dened as those
that occurred in at least two patients in at
least one of the treatment groups) were
hyperlipidaemia, dyslipidaemia, nasophar-
yngitis, upper respiratory tract infection,
diabetes mellitus, hyperuricaemia, dizziness,
headache, blood glucose increase and the
presence of protein in urine (Table 3). Most
AEs were of mild intensity. Treatment-
related AEs occurred in four (2.4%) patients
in the A5 group and in three (1.9%)
patients in the T80/A5 group; headache
(two patients [1.2%] in the A5 group, one
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Journal of International Medical Research 42(1)
patient [0.6%] in the T80/A5 group), per-
ipheral oedema (one patient in each group,
0.6%), cough (one patient [0.3%] in the A5
group, none in the T80/A5 group) and
epistaxis (none in the A5 group, one patient
[0.6%] in the T80/A5 group).
There were no reports of death or serious
AEs during the randomized treatment
period. Discontinuation due to AEs (all
considered as signicant AEs according to
ICH E325) occurred for two patients (1.2%)
in the A5 group (cough [n 1] and headache
[n 1]) and one patient (0.6%) in the T80/
A5 mg group (epistaxis). One patient (0.6%)
in the T80/A5 mg group had a signicant AE
of hypokalaemia, which did not result in
study discontinuation.
There were no clinically important dier-
ences in laboratory parameters between the
two treatment groups during the rando-
mized treatment period. Changes from base-
line to the end of treatment in pulse rate
were small and similar in both treatment
groups.
Discussion
In the present trial, as expected, patients
who were randomized to A5 monotherapy
continued to have a benet on BP control
during the 8 weeks randomized treatment
period, even though they did not respond
adequately to the 6-week open-label treat-
ment. In non-responder trials, further BP
reduction during the double-blind treatment
phase in those patients who continue to
receive the same monotherapy as in the run-
in phase is a common observation.22,23,2628
This is due not only to the placebo eect but
also to the regression-to-the-mean phenom-
enon. The crucial factor in such trials is to
demonstrate a statistically signicant and
clinically relevant additional BP reduction in
response to the combination therapy in
patients who did not respond adequately
to standard therapeutic doses of the
monotherapy.29
Zhu et al. 61

Figure 3. Proportion of patients at baseline, week 4 and week 8 achieving goals for (A) diastolic blood
pressure (DBP) and (B) systolic blood pressure (SBP) in 314 Asian patients enrolled in a randomized, double-
blind study to evaluate the efficacy of a single-pill combination of telmisartan 80 mg plus amlodipine 5 mg (T80/
A5) compared with amlodipine 5 mg monotherapy (A5). DBP goal, <90 mmHg; SBP goal, <140 mmHg;
Fishers exact test; P  0.05.

In the present study, the T80/A5 single-
pill combination was signicantly more
eective than continued A5 monotherapy
in further lowering the BP in Asian patients
with hypertension whose BP was not ade-
quately controlled during 6 weeks of A5
monotherapy. The T80/A5 single-pill com-
bination was also signicantly more eective
than A5 monotherapy in a subset of Chinese
patients. T80/A5 single-pill combination
treatment resulted in signicantly higher
adjusted mean dierences between baseline
and week 8 in DBP and SBP than A5
monotherapy. The BP goal attainment rate
and response rates at the end of 8 weeks were
signicantly higher in the T80/A5 single-pill
combination group than in the A5 group.
The results of the present study are
consistent with those observed in previous
international studies conducted in patients
with hypertension not controlled on amlo-
dipine monotherapy. In those studies,
telmisartan/amlodipine single-pill combin-
ation has been shown to result in superior
BP reduction and achievement of BP goal
and response rates.2023 The telmisartan/
amlodipine combination also provides
superior 24-h BP lowering compared with
either drug administered as monotherapy
in patients with mild to moderate
hypertension.24
The ecacy and favourable safety prole
of the ARB/amlodipine combination has
been shown in a wide variety of patients,
including those with severe hypertension,
those at added risk of CV events3037 and in
the elderly.38 The T80/A10 combination
resulted in a greater decrease in BP, and in
higher BP goal rates, compared with amlo-
dipine monotherapy in patients with

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62 Journal of International Medical Research 42(1)

Figure 4. Proportion of patients at baseline, week 4 and week 8 achieving responses for (A) diastolic blood
pressure (DBP) and (B) systolic blood pressure (SBP) in 314 Asian patients enrolled in a randomized, double-
blind study to evaluate the efficacy of a single-pill combination of telmisartan 80 mg plus amlodipine 5 mg (T80/
A5) compared with amlodipine 5 mg monotherapy (A5). DBP response, <90 mmHg or reduction from
baseline 10 mmHg; SBP response, <140 mmHg or reduction from baseline 15 mmHg; Fishers exact test;
P  0.05.

diabetes and hypertension.35 The telmisar-
tan/amlodipine combination was also
shown to be well tolerated, to reduce BP
eectively, and to enable the majority of
hypertensive patients with obesity, diabetes
or the metabolic syndrome to achieve target
BP in a post hoc subgroup analysis of data
from 13 clinical trials.36
Response to antihypertensive treatment
may vary among dierent ethnic groups. In
a pre-specied analysis of the BP-lowering
arm of the Anglo-Scandinavian Cardiac
Outcomes Trial (ASCOT-BPLA), import-
ant dierences in BP responses were
observed among ethnic groups with regard
to treatment with atenolol (as rst-line) and
perindopril (as an add-on to amlodipine),
while response to amlodipine as rst-line,
and thiazide diuretics as an add-on, did not
vary.39 In the present study, there were no
dierences observed between the overall
Asian population and the Chinese subgroup
for any measure.
Overall, double-blind treatment with
either A5 or T80/A5 for 8 weeks was well
tolerated in the present study. The safety
and tolerability data obtained were consist-
ent with the known proles of telmisartan
and amlodipine, and no clinically important
dierences were noted in safety and toler-
ability between the A5 group and the
T80/A5 group in the 8-week double-blind,
randomized treatment period. In previous
studies, telmisartan/amlodipine single-pill
combination treatment was associated with
a lower incidence of peripheral oedema than
amlodipine monotherapy.2023 In the pre-
sent study, the incidence of peripheral
oedema was low, and was reported in one
patient in each group.

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Zhu et al. 63

Table 3. Adverse events (AEs) that occurred in at

least two patients in either treatment group in the Acknowledgements
randomized treatment period, in those enrolled in a The authors were fully responsible for all content
randomized, double-blind study to evaluate the and editorial decisions, were involved at all stages
efficacy of a single-pill combination of telmisartan of manuscript development and have approved
80 mg plus amlodipine 5 mg (T80/A5) compared
the nal version. Medical writing assistance was
with amlodipine 5 mg monotherapy (A5).
provided by Dr Lakshmi Venkatraman of
Treatment group PAREXEL during the preparation of this article.
The authors meet criteria for authorship as
A5 T80/A5 recommended by the International Committee
MedDRA-preferred term n 164 n 160 of Medical Journal Editors (ICMJE) and
Total with AEs 33 (20.1) 33 (20.6) received no compensation related to the devel-
Hyperlipidaemia 6 (3.7) 5 (3.1) opment of the manuscript. The authors thank the
Dyslipidaemia 5 (3.0) 2 (1.3) study participants without whom this study
Nasopharyngitis 3 (1.8) 2 (1.3) would not have been possible, and the following
Upper respiratory 2 (1.2) 0 (0.0) investigators for their participation:
tract infection China: Dr Chen Jun Zhu, Dr Dai Qiuyan,
Diabetes mellitus 2 (1.2) 2 (1.3) Dr Dong Yugang, Dr Gu Shuiming, Dr Hu
Hyperuricaemia 2 (1.2) 1 (0.6) Dayi, Dr Li Hongwei, Dr Li Huimin, Dr Li
Dizziness 1 (0.6) 3 (1.9)
Zhanquan, Dr Luo Ming, Dr Zhang Yu, Dr Zhao
Headache 2 (1.2) 1 (0.6)
Shui Ping, Dr Zhu Dingliang; Malaysia:
Blood glucose increasea 1 (0.6) 4 (2.5)
Protein urine present 2 (1.2) 1 (0.6) Dr Azhari Rosman, Dr Jeyaindran Sinnadurai;
Philippines: Dr Marcelito Durante, Dr Philip U.
Data presented as n (%) of patients. Chua.
a
All increases were mild and were considered to be
unrelated to treatment.
MedDRA, Medical Dictionary for Drug Regulatory Affairs Declaration of conflicting interest
version 14.0.
Dr Zhu and Dr Gao declare that they have no
The present study included only Chinese, conicts of interest. Dr Holtbruegge is a statis-
Malaysian and Philippine patients, which tical consultant for Boehringer Ingelheim
may limit the applicability of the ndings to Pharma GmbH & Co.KG, Germany.
patients from other Asian countries. In Dr Huang is an employee of Boehringer
addition, the controlled nature of the study Ingelheim, International Trading (Shanghai)
limits generalization of the results to those Co., Ltd, China.
categories of patients who were excluded
from the study.
In conclusion, 8 weeks of treatment with Funding
T80/A5 single-pill combination provided Medical writing assistance was supported nan-
superior BP-lowering ecacy compared cially by Boehringer Ingelheim Pharma
with A5 monotherapy for Asian patients International GmbH & Co. KG.
whose BP was not controlled with A5
monotherapy. Results were consistent in
the subset of Chinese patients. The safety Previous presentations
and tolerability prole of T80/A5 single-pill The study results were previously presented at
combination is comparable to that of A5 the 24th Scientic Meeting of the International
monotherapy and consistent with that Society of Hypertension held in Sydney,
reported in previous studies. Australia, from 30 September to 4 October 2012.

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64
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