SMOOTH - Blood Pressure Control in Diabetic/Obese Patients

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Completed

CT.gov ID

NCT00239538

Collaborator

(none)

840

Enrollment

102

Locations

Duration (Months)

8.2

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to demonstrate that telmisartan 80 mg combined with hydrochlorothiazide 12.5 mg (T80/H12.5) is at least as effective and possibly superior to valsartan 160 mg combined with hydrochlorothiazide 12.5 mg (V160/H12.5) in lowering mean ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) during the last 6 hours of the 24-hour dosing interval at the end of a 10-week treatment period in mild-to-moderate hypertensive, overweight or obese patients with type 2 diabetes mellitus

Condition or Disease	Intervention/Treatment	Phase
Hypertension Diabetes Mellitus, Type 2	Drug: telmisartan combined with hydrochlorothiazide (80/12.5 mg) Drug: valsartan combined with hydrochlorothiazide (160/12.5mg)	Phase 4

Detailed Description

Methodology:

Prospective, randomised, open-label, blinded end-point, forced-titration, parallel group comparison using Ambulatory Blood Pressure Monitoring (ABPM).

Planned/Actual Number of Subjects:

Enrolled: 1500/2085; Randomised: 750/840; Complete: 680/752

Diagnosis and Main Criteria for Inclusion:

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.
At least 30 years of age.

Duration of Treatment:

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.

Criteria for Efficacy:

Primary Endpoint:

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.

Secondary Endpoints:

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 clock time) 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 dose time).

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.

Criteria for Safety:

Evaluation of adverse events, physical examinations, laboratory assessments, pulse rate and cuff blood pressure monitoring.

Statistical Method:

Analysis of covariance with treatment and centre as main effects and baseline as a covariate; Mantel-Haenszel test controlling for centre.

Study Hypothesis:

Null Hypothesis:

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).

Alternative Hypothesis:

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).

Comparison(s):

Telmisartan (80 mg) plus hydrochlorothiazide (12.5 mg) vs. valsartan (160 mg) plus hydrochlorothiazide (12.5 mg)

Study Design

Study Type:

Interventional

Actual Enrollment :

840 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Prospective, Randomized, Open-label, Blinded Endpoint, Forced Titration Study to Compare Telmisartan Combined With HCTZ (80mg/12.5mg), to Valsartan Combined With HCTZ (160mg/12.5mg), for the Control of Mild-to-moderate Hypertension in Obese Patients With Type 2 Diabetes Mellitus Using ABPM.

Study Start Date :

Jan 1, 2003

Actual Primary Completion Date :

Dec 1, 2004

Study Completion Date :

Dec 1, 2004

Outcome Measures

Primary Outcome Measures

Changes from baseline in the mean SBP and DBP as measured by ambulatory blood pressure monitoring (ABPM) [10 weeks]

Secondary Outcome Measures

Changes from baseline in the last 6-hour ABPM mean (relative to dose time) pulse pressure. [10 weeks]
Changes from baseline in the 24-hour ABPM mean (relative to dose time) for SBP, DBP and pulse pressure. [10 weeks]
Changes from baseline in the ABPM mean (relative to clock time) for SBP, DBP, and pulse pressure during the morning, daytime and night time periods of the 24-hour dosing interval. [10 weeks]
Changes from baseline in SBP and DBP load during the 24-hour dosing interval. [10 weeks]
Responder rates based on the 24-hour ABPM mean (relative to dose time) blood pressures defined [10 weeks]
In-clinic trough cuff blood pressure measures at the end of both a 4-week (Visit 4) treatment period and a 10-week (Visit 6) treatment period. [4 weeks and 10 weeks]
Responder rates based on the mean seated trough cuff measurements [4 weeks and 10 weeks]
Metabolic and inflammatory marker changes from baseline [up to 10 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Ability to provide written informed consent.
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.
24-hour mean DBP of >= 85 mmHg, and/or SBP = 130 mmHg, measured by ABPM at Visit 3.
30 years of age or greater.
Ability to stop current antihypertensive therapy and other disallowed medications without risk to the patient.
Diagnosis of type-2 diabetes mellitus with HbA1C less than or equal to 10%.
Overweight or obese as defined by a BMI >= 27 kg/m2 in non-Asians and >= 24 kg/m2 in Asians.
Negative UPT for females.

Exclusion Criteria:

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.
Night shift workers
Mean sitting SBP >= 180 mmHg or mean sitting DBP >= 110 mmHg during any visit of the placebo run-in period.
Known or suspected secondary hypertension. Hepatic and/or renal dysfunction
Fasting serum glucose > 17 mmol/l (or 300 mg/dl) at visit 2
Bilateral renal artery stenosis, renal artery stenosis in a solitary kidney, patients on dialysis or post-renal transplant patients.
Clinically relevant sodium depletion, hypokalaemia or hyperkalaemia.
Uncorrected volume depletion.
Primary aldosteronism.
Hereditary fructose intolerance.
Biliary obstructive disorders (e.g., cholestasis).
Congestive heart failure
Stroke within the past six months.
Documented severe obstructive coronary artery disease.
Myocardial infarction, cardiac surgery or unstable angina within the past three months.
PCI (percutaneous coronary intervention) within the past three months or planned during trial period.
Sustained ventricular tachycardia, atrial fibrillation, atrial flutter or other clinically relevant cardiac arrhythmias.
Hypertrophic obstructive cardiomyopathy, aortic stenosis, hemodynamically relevant stenosis of the aortic or mitral valve.
Patients with type-1 diabetes mellitus.
Patients who have previously experienced symptoms of angioedema during ACE or ARB treatment.
History of drug or alcohol dependency in past six months.
Chronic administration of any medications known to affect blood pressure, except medication allowed by the protocol.
Any investigational drug therapy within the past month.
Known hypersensitivity to any component of the study drug.
Concurrent use of corticosteroids, colestipol or cholestyramine resins.
Any clinical condition which would not allow safe completion of the protocol.
Inability to comply with the protocol.
Any surgery that is, at the time of screening, planned to take place during the study period.
History of non-compliance with prescribed medications.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cooper Green Hospital	Birmingham	Alabama	United States	35223
2	Boehringer Ingelheim Investigational Site	Birmingham	Alabama	United States	35294-2041
3	Boehringer Ingelheim Investigational Site	Huntsville	Alabama	United States	35801
4	Boehringer Ingelheim Investigational Site	Mobile	Alabama	United States	36608
5	Boehringer Ingelheim Investigational Site	Glendale	Arizona	United States	85306
6	Boehringer Ingelheim Investigational Site	Tucson	Arizona	United States	85712
7	Memorial Research Medical Clinic	Long Beach	California	United States	90806
8	1200	Los Angeles	California	United States	90033
9	Boehringer Ingelheim Investigational Site	Los Angeles	California	United States	90057
10	8615	Nuena Park	California	United States	90620
11	Boehringer Ingelheim Investigational Site	Orange	California	United States	92868
12	Boehringer Ingelheim Investigational Site	Sacramento	California	United States	95825
13	Boehringer Ingelheim Investigational Site	Sacramento	California	United States	95841
14	595	San Francisco	California	United States	94132
15	1805	Stockton	California	United States	95204
16	Boehringer Ingelheim Investigational Site	Torrance	California	United States	90505
17	2311	Washington	District of Columbia	United States	20037
18	Boehringer Ingelheim Investigational Site	Fort Lauderdale	Florida	United States	33308
19	Boehringer Ingelheim Investigational Site	Ft. Lauderdale	Florida	United States	33308-4311
20	6448	Hollywood	Florida	United States	33023
21	Boehringer Ingelheim Investigational Site	Melbourne	Florida	United States	32901
22	Attention: Larry I. Gilderman, D.O.	Pembroke Pines	Florida	United States	33024
23	Boehringer Ingelheim Investigational Site	Pembroke Pines	Florida	United States	33027
24	Boehringer Ingelheim Investigational Site	Pembroke Pines	Florida	United States	33028
25	Boehringer Ingelheim Investigational Site	Pinellas Park	Florida	United States	33781
26	Boehringer Ingelheim Investigational Site	West Palm Beach	Florida	United States	33401
27	Herron Medical Center, Ltd.	Chicago	Illinois	United States	60610
28	Boehringer Ingelheim Investigational Site	Chicago	Illinois	United States	60612
29	Boehringer Ingelheim Investigational Site	Orland Park	Illinois	United States	60462
30	Boehringer Ingelheim Investigational Site	Evansville	Indiana	United States	47710
31	Boehringer Ingelheim Investigational Site	Evansville	Indiana	United States	47713
32	Boehringer Ingelheim Investigational Site	Shawnee	Kansas	United States	66216
33	Boehringer Ingelheim Investigational Site	Wichita	Kansas	United States	67212
34	Boehringer Ingelheim Investigational Site	New Orleans	Louisiana	United States	70119
35	Boehringer Ingelheim Investigational Site	Baltimore	Maryland	United States	21204
36	200	Baltimore	Maryland	United States	21218
37	Boehringer Ingelheim Investigational Site	Kansas City	Missouri	United States	64114
38	12401	St.Louis	Missouri	United States	63141
39	Boehringer Ingelheim Investigational Site	Missoula	Montana	United States	59802
40	Boehringer Ingelheim Investigational Site	Brooklyn	New York	United States	11203
41	3	Buffalo	New York	United States	14209
42	Comprehensive Clinical Research	Berlin	North Carolina	United States	08009
43	Boehringer Ingelheim Investigational Site	Winston Salem	North Carolina	United States	27103
44	Boehringer Ingelheim Investigational Site	Kettering	Ohio	United States	45429
45	Boehringer Ingelheim Investigational Site	Marion	Ohio	United States	43302
46	Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma	United States	73132-4904
47	Boehringer Ingelheim Investigational Site	Portland	Oregon	United States	97232
48	Boehringer Ingelheim Investigational Site	Broomal	Pennsylvania	United States	19008
49	6605	Bartlett	Tennessee	United States	38134
50	108	Fayetteville	Tennessee	United States	37334
51	Boehringer Ingelheim Investigational Site	Carrollton	Texas	United States	75006
52	7777	Dallas	Texas	United States	75230
53	Boehringer Ingelheim Investigational Site	El Paso	Texas	United States	79912
54	Team Research of Texas	Harker Heights	Texas	United States	76548
55	Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States	78217
56	Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States	78229-4801
57	420	Salt Lake City	Utah	United States	84111
58	20901	Ettrick	Virginia	United States	23803
59	Boehringer Ingelheim Investigational Site	Spokane	Washington	United States	99207
60	5000	Miwaukee	Wisconsin	United States	53295
61	Boehringer Ingelheim Investigational Site	BsAs		Argentina	C1425AST
62	Boehringer Ingelheim Investigational Site	Coronel Suárez		Argentina	7540
63	Boehringer Ingelheim Investigational Site	Rosario, Sta. Fe		Argentina	2000
64	Boehringer Ingelheim Investigational Site	Kippa-Ring	Queensland	Australia	4021
65	Emeritus Research	Malvern	Victoria	Australia	3144
66	Boehringer Ingelheim Investigational Site	Prahran	Victoria	Australia	3181
67	Boehringer Ingelheim Investigational Site	Calgary	Alberta	Canada	T2N 2T9
68	Boehringer Ingelheim Investigational Site	Conquitlam	British Columbia	Canada	V3K 3V9
69	Dr. Hugh Tildesley	Vancouver	British Columbia	Canada	V6E 1M7
70	Boehringer Ingelheim Investigational Site	Vancouver	British Columbia	Canada	V6Z 1Y8
71	Boehringer Ingelheim Investigational Site	Bay Roberts	Newfoundland and Labrador	Canada	A0A 1G0
72	Boehringer Ingelheim Investigational Site	Mount Pearl	Newfoundland and Labrador	Canada	A1N 2C3
73	Boehringer Ingelheim Investigational Site	Halifax	Nova Scotia	Canada	B3H2Y9
74	Boehringer Ingelheim Investigational Site	Hamilton	Ontario	Canada	L8M 1K7
75	Boehringer Ingelheim Investigational Site	Kitchener	Ontario	Canada	N2H 2P2
76	Boehringer Ingelheim Investigational Site	London	Ontario	Canada	N6G 2M3
77	Boehringer Ingelheim Investigational Site	London	Ontario	Canada	N6G 2V2
78	Boehringer Ingelheim Investigational Site	Mississauga	Ontario	Canada	L5K 2N6
79	Boehringer Ingelheim Investigational Site	North York	Ontario	Canada	M3J 1N2
80	Boehringer Ingelheim Investigational Site	Oakville	Ontario	Canada	L6H 3P1
81	Boehringer Ingelheim Investigational Site	Orleans	Ontario	Canada	K1C 1S6
82	Boehringer Ingelheim Investigational Site	Sarnia	Ontario	Canada	N7T 4X3
83	LMC Thornhill	Thornhill	Ontario	Canada	L4J 1V8
84	Boehringer Ingelheim Investigational Site	Thunder Bay	Ontario	Canada	P7E 6E7
85	Boehringer Ingelheim Investigational Site	Toronto	Ontario	Canada	M4R 2G4
86	91 Thomas-Chapais	Boucherville	Quebec	Canada	J4B 6P3
87	Boehringer Ingelheim Investigational Site	Montreal	Quebec	Canada	H2W 1T7
88	Pavillon St. Sacrement	Sainte-Foy	Quebec	Canada	G1S 4L8
89	Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan	Canada	S7K 3H3
90	Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan	Canada	S7K 7H9
91	c/o Hemodynamics Offices	Saskatoon	Saskatchewan	Canada	S7N 0W8
92	Inje University Pusan Hospital	Busan		Korea, Republic of
93	Yeungnam University Medical Center	Daegu		Korea, Republic of	705717
94	Korea University Medical Center	Seoul		Korea, Republic of	136705
95	Boehringer Ingelheim Investigational Site	Col. Del Valle		Mexico	CP 03100
96	Boehringer Ingelheim Investigational Site	Col. Magdalena de las Salinas		Mexico	C.P 07300
97	Boehringer Ingelheim Investigational Site	Col. Sección 16, México, D.F.		Mexico	C.P. 14000
98	Boehringer Ingelheim Investigational Site	Guadalajara, Jalisco		Mexico	C.P 44700
99	Boehringer Ingelheim Investigational Site	Zapopan, Jalisco		Mexico	45100
100	Boehringer Ingelheim Investigational Site	Auckland		New Zealand
101	1st Floor Hagely Hostel	Christchurch		New Zealand
102	National Taiwan University Hospital	Taipei		Taiwan