Hypertension affects approximately one billion people worldwide. There is a strong
relationship between high blood pressure (BP) and cardiovascular disease (CVD) risk and
lowering BP can reduce this risk. This is especially important for hypertensive patients with
other risk factors for CVD, such as diabetes and obesity, as these factors act additively to
further increase CVD risk. In these "at-risk" patients, it has been recommended that BP
should be reduced to less than 130/80 mmHg. To achieve this target, multiple antihypertensive
medications are often required. The American Diabetes Association recommends that such a
therapy should include BP medications from the ACE or ARB classes, depending on which is best
tolerated. If BP targets remain unmet, a combination therapy that includes medication from
the thiazide diuretic class is further recommended.
Telmisartan and valsartan are potent BP medications from the ARB class. Of note, telmisartan
belongs to the second generation of ARBs with sustained 24-hr BP protection, including the
early morning hours during which patients are at increased risk for cardiovascular
complications. Telmisartan and valsartan are also available in combination with the diuretic
hydrochlorothiazide (MICARDIS® PLUS/ MICARDIS® HCT and DIOVAN HCT®). Such formulations have
an additive action and are able to produce greater BP reductions than either product alone
and are particularly useful in at-risk patients where additional efficacy is needed to
achieve BP control.
Given the above, the primary objective of the SMOOTH study was to demonstrate that, when
combined with hydrochlorothiazide (12. 5 mg), telmisartan (80 mg) is at least as effective and
possibly superior to valsartan (160 mg) in lowering systolic and diastolic BP during the last
6 hours of the 24-hour dosing interval (i. e., the critical morning period) following a
10-week treatment period in hypertensive, overweight/obese Type-2 diabetics.
Prospective, randomised, open-label, blinded end-point, forced-titration, parallel group
comparison using Ambulatory Blood Pressure Monitoring (ABPM).
1) Mild-to-moderate hypertension defined as a baseline mean seated cuff DBP of 95 - 109
(inclusive) mmHg, and/or SBP of 140-179 (inclusive) mmHg, and a baseline 24-hour ABPM mean
DBP >= 85 mmHg, and/or SBP >= 130 mmHg. 2) Overweight or obese as defined by a Body Mass
Index (BMI) >= 27 kg/m2 in non-Asians and >= 24 kg/m2 in Asians 3) Type-2 diabetes mellitus.
4) At least 30 years of age.
10 weeks total: telmisartan (80 mg) or valsartan (160 mg) for 4 weeks followed by telmisartan
(80 mg) plus hydrochlorothiazide (12. 5 mg) or valsartan (160 mg) plus hydrochlorothiazide
(12. 5 mg) for an additional 6 weeks.
Reductions in blood pressure during the last 6 hours of the 24-hour dosing interval as
measured by ABPM. The primary analysis will consist of comparing telmisartan combined with
hydrochlorothiazide 80 mg/12. 5 mg to valsartan combined with hydrochlorothiazide 160 mg/12. 5
mg at the end of the 10-week study using a closed testing procedure first testing for
non-inferiority based on SBP; if significant, testing for non-inferiority based on DBP; if
significant, testing for superiority based on SBP; and if significant, testing for
superiority based on DBP.
Statistically greater reductions in ambulatory blood pressure for patients treated with
telmisartan combined with hydrochlorothiazide 80 mg/12. 5 mg compared to patients treated with
valsartan combined with hydrochlorothiazide 160 mg/12. 5 mg at the end of the 10-week study as
measured by: 1) Changes from baseline in the last 6 hours of the 24-hour dosing interval for
pulse pressure; 2) Changes from baseline in the 24-hour ABPM mean (relative to dose time) for
SBP, DBP, and pulse pressure; 3) Changes from baseline in the ABPM mean SBP, DBP, and pulse
pressure (relative to clocktime) during other periods (i. e. morning, daytime, night time) of
the 24-hour dosing interval; 4) Change from baseline in systolic and diastolic blood pressure
load during the 24-hour dosing interval; and 5) Percentage of patients responding to
treatment based on the 24-hour ABPM mean SBP and DBP (relative to dosetime).
Statistically greater reduction in mean seated trough blood pressure patients treated with
telmisartan combined with hydrochlorothiazide 80 mg/12. 5 mg compared to patients treated with
valsartan combined with hydrochlorothiazide 160 mg/12. 5 mg at the end of the 10-week study as
measured by: 1) Changes from baseline in mean seated trough SBP and DBP as determined by
electronic or manual device in-clinic; and 2) Percentage of patients responding to treatment
based on electronic or manual in-clinic trough cuff blood pressures.
Evaluation of other endpoints comparing telmisartan combined with hydrochlorothiazide 80
mg/12. 5 mg to valsartan combined with hydrochlorothiazide 160 mg/12. 5 mg, respectively,
including: 1) Changes from baseline in metabolic markers: serum TG, LDL-C, HDL-C, total
cholesterol, potassium, fasting glucose and HbA1C, and for urine: Na, K, Cl, proteinuria (as
measured by spot urine for protein: creatinine ratio); and 2) inflammatory markers: serum high
sensitive C-reactive protein, serum homocysteine and plasma fibrinogen.
Evaluation of adverse events, physical examinations, laboratory assessments, pulse rate and
cuff blood pressure monitoring.
Analysis of covariance with treatment and centre as main effects and baseline as a covariate;
Mantel-Haenszel test controlling for centre.
The overall mean change from baseline in the automated blood pressure monitor mean blood
pressure during the last 6 hours of the 24-hour dosing interval for telmisartan (80 mg) plus
hydrochlorothiazide (12. 5 mg) is less than or equal to that for valsartan (160 mg) plus
hydrochlorothiazide (12. 5 mg).
The overall mean change from baseline in the automated blood pressure monitor mean blood
pressure during the last 6 hours of the 24-hour dosing interval for telmisartan (80 mg) plus
hydrochlorothiazide (12. 5 mg) is greater than that for valsartan (160 mg) plus
hydrochlorothiazide (12. 5 mg).
Telmisartan (80 mg) plus hydrochlorothiazide (12. 5 mg) vs. valsartan (160 mg) plus
hydrochlorothiazide (12. 5 mg)
INCLUSION CRITERIA
1. Ability to provide written informed consent.
2. Hypertension defined as a mean seated DBP of 95-109 (inclusive) mmHg, and/or SBP of
140-179 (inclusive) mmHg, measured by BpTRU electronic or manual cuff at Visit 2.
3. 24-hour mean DBP of >= 85 mmHg, and/or SBP = 130 mmHg, measured by ABPM at Visit 3.
4. 30 years of age or greater.
5. Ability to stop current antihypertensive therapy and other disallowed medications
without risk to the patient.
6. Diagnosis of type-2 diabetes mellitus with HbA1C less than or equal to 10%.
7. Overweight or obese as defined by a BMI >= 27 kg/m2 in non-Asians and >= 24 kg/m2 in
Asians.
8. Negative UPT for females.
EXCLUSION CRITERIA
1. Pre-menopausal women, not surgically sterile or, not nursing/pregnant or are of
child-bearing potential and will not practice acceptable methods of birth control
during study.
2. Night shift workers
3. Mean sitting SBP >= 180 mmHg or mean sitting DBP >= 110 mmHg during any visit of the
placebo run-in period.
4. Known or suspected secondary hypertension. Hepatic and/or renal dysfunction
5. Fasting serum glucose > 17 mmol/l (or 300mg/dl) at visit 2
6. Bilateral renal artery stenosis, renal artery stenosis in a solitary kidney, patients
on dialysis or post-renal transplant patients.
7. Clinically relevant sodium depletion, hypokalaemia or hyperkalaemia.
8. Uncorrected volume depletion.
9. Primary aldosteronism.
10. Hereditary fructose intolerance.
11. Biliary obstructive disorders (e. g. cholestasis).
12. Congestive heart failure
13. Stroke within the past six months.
14. Documented severe obstructive coronary artery disease.
15. Myocardial infarction, cardiac surgery or unstable angina within the past three
months.
16. PCI (percutaneous coronary intervention) within the past three months or planned
during trial period.
17. Sustained ventricular tachycardia, atrial fibrillation, atrial flutter or other
clinically relevant cardiac arrhythmias.
18. Hypertrophic obstructive cardiomyopathy, aortic stenosis, hemodynamically relevant
stenosis of the aortic or mitral valve.
19. Patients with type-1 diabetes mellitus.
20. Patients who have previously experienced symptoms of angioedema during ACE or ARB
treatment.
21. History of drug or alcohol dependency in past six months.
22. Chronic administration of any medications known to affect blood pressure, except
medication allowed by the protocol.
23. Any investigational drug therapy within the past month.
24. Known hypersensitivity to any component of the study drug.
25. Concurrent use of corticosteroids, colestipol or cholestyramine resins.
26. Any clinical condition which would not allow safe completion of the protocol.
27. Inability to comply with the protocol.
29. Any surgery that is, at the time of screening, planned to take place during the study
period.
30. History of non-compliance with prescribed medications.
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