SMOOTH - Blood Pressure Control in Diabetic/Obese Patients

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.

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

Study Overview

• Status: Completed
• Conditions: Hypertension; Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: telmisartan combined with hydrochlorothiazide (80/12.5 mg); Drug: valsartan combined with hydrochlorothiazide (160/12.5mg)

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:

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.

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 Type: Interventional
• Enrollment (Actual): 840
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • BsAs, Argentina, C1425AST
    • Boehringer Ingelheim Investigational Site
  • Coronel Suárez, Argentina, 7540
    • Boehringer Ingelheim Investigational Site
  • Rosario, Sta. Fe, Argentina, 2000
    • Boehringer Ingelheim Investigational Site
• Australia
  • Queensland
    • Kippa-Ring, Queensland, Australia, 4021
      • Boehringer Ingelheim Investigational Site
  • Victoria
    • Malvern, Victoria, Australia, 3144
      • Emeritus Research
    • Prahran, Victoria, Australia, 3181
      • Boehringer Ingelheim Investigational Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Boehringer Ingelheim Investigational Site
  • British Columbia
    • Conquitlam, British Columbia, Canada, V3K 3V9
      • Boehringer Ingelheim Investigational Site
    • Vancouver, British Columbia, Canada, V6E 1M7
      • Dr. Hugh Tildesley
    • Vancouver, British Columbia, Canada, V6Z 1Y8
      • Boehringer Ingelheim Investigational Site
  • Newfoundland and Labrador
    • Bay Roberts, Newfoundland and Labrador, Canada, A0A 1G0
      • Boehringer Ingelheim Investigational Site
    • Mount Pearl, Newfoundland and Labrador, Canada, A1N 2C3
      • Boehringer Ingelheim Investigational Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H2Y9
      • Boehringer Ingelheim Investigational Site
  • Ontario
    • Hamilton, Ontario, Canada, L8M 1K7
      • Boehringer Ingelheim Investigational Site
    • Kitchener, Ontario, Canada, N2H 2P2
      • Boehringer Ingelheim Investigational Site
    • London, Ontario, Canada, N6G 2M3
      • Boehringer Ingelheim Investigational Site
    • London, Ontario, Canada, N6G 2V2
      • Boehringer Ingelheim Investigational Site
    • Mississauga, Ontario, Canada, L5K 2N6
      • Boehringer Ingelheim Investigational Site
    • North York, Ontario, Canada, M3J 1N2
      • Boehringer Ingelheim Investigational Site
    • Oakville, Ontario, Canada, L6H 3P1
      • Boehringer Ingelheim Investigational Site
    • Orleans, Ontario, Canada, K1C 1S6
      • Boehringer Ingelheim Investigational Site
    • Sarnia, Ontario, Canada, N7T 4X3
      • Boehringer Ingelheim Investigational Site
    • Thornhill, Ontario, Canada, L4J 1V8
      • LMC Thornhill
    • Thunder Bay, Ontario, Canada, P7E 6E7
      • Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada, M4R 2G4
      • Boehringer Ingelheim Investigational Site
  • Quebec
    • Boucherville, Quebec, Canada, J4B 6P3
      • 91 Thomas-Chapais
    • Montreal, Quebec, Canada, H2W 1T7
      • Boehringer Ingelheim Investigational Site
    • Sainte-Foy, Quebec, Canada, G1S 4L8
      • Pavillon St. Sacrement
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7K 3H3
      • Boehringer Ingelheim Investigational Site
    • Saskatoon, Saskatchewan, Canada, S7K 7H9
      • Boehringer Ingelheim Investigational Site
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • c/o Hemodynamics Offices
• Korea, Republic of
  • Busan, Korea, Republic of
    • Inje University Pusan Hospital
  • Daegu, Korea, Republic of, 705717
    • Yeungnam University Medical Center
  • Seoul, Korea, Republic of, 136705
    • Korea University Medical Center
• Mexico
  • Col. Del Valle, Mexico, CP 03100
    • Boehringer Ingelheim Investigational Site
  • Col. Magdalena de las Salinas, Mexico, C.P 07300
    • Boehringer Ingelheim Investigational Site
  • Col. Sección 16, México, D.F., Mexico, C.P. 14000
    • Boehringer Ingelheim Investigational Site
  • Guadalajara, Jalisco, Mexico, C.P 44700
    • Boehringer Ingelheim Investigational Site
  • Zapopan, Jalisco, Mexico, 45100
    • Boehringer Ingelheim Investigational Site
• New Zealand
  • Auckland, New Zealand
    • Boehringer Ingelheim Investigational Site
  • Christchurch, New Zealand
    • 1st Floor Hagely Hostel
• Taiwan
  • Taipei, Taiwan
    • National Taiwan University Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35223
      • Cooper Green Hospital
    • Birmingham, Alabama, United States, 35294-2041
      • Boehringer Ingelheim Investigational Site
    • Huntsville, Alabama, United States, 35801
      • Boehringer Ingelheim Investigational Site
    • Mobile, Alabama, United States, 36608
      • Boehringer Ingelheim Investigational Site
  • Arizona
    • Glendale, Arizona, United States, 85306
      • Boehringer Ingelheim Investigational Site
    • Tucson, Arizona, United States, 85712
      • Boehringer Ingelheim Investigational Site
  • California
    • Long Beach, California, United States, 90806
      • Memorial Research Medical Clinic
    • Los Angeles, California, United States, 90033
      • 1200
    • Los Angeles, California, United States, 90057
      • Boehringer Ingelheim Investigational Site
    • Nuena Park, California, United States, 90620
      • 8615
    • Orange, California, United States, 92868
      • Boehringer Ingelheim Investigational Site
    • Sacramento, California, United States, 95825
      • Boehringer Ingelheim Investigational Site
    • Sacramento, California, United States, 95841
      • Boehringer Ingelheim Investigational Site
    • San Francisco, California, United States, 94132
      • 595
    • Stockton, California, United States, 95204
      • 1805
    • Torrance, California, United States, 90505
      • Boehringer Ingelheim Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • 2311
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Boehringer Ingelheim Investigational Site
    • Ft. Lauderdale, Florida, United States, 33308-4311
      • Boehringer Ingelheim Investigational Site
    • Hollywood, Florida, United States, 33023
      • 6448
    • Melbourne, Florida, United States, 32901
      • Boehringer Ingelheim Investigational Site
    • Pembroke Pines, Florida, United States, 33024
      • Attention: Larry I. Gilderman, D.O.
    • Pembroke Pines, Florida, United States, 33027
      • Boehringer Ingelheim Investigational Site
    • Pembroke Pines, Florida, United States, 33028
      • Boehringer Ingelheim Investigational Site
    • Pinellas Park, Florida, United States, 33781
      • Boehringer Ingelheim Investigational Site
    • West Palm Beach, Florida, United States, 33401
      • Boehringer Ingelheim Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60610
      • Herron Medical Center, Ltd.
    • Chicago, Illinois, United States, 60612
      • Boehringer Ingelheim Investigational Site
    • Orland Park, Illinois, United States, 60462
      • Boehringer Ingelheim Investigational Site
  • Indiana
    • Evansville, Indiana, United States, 47710
      • Boehringer Ingelheim Investigational Site
    • Evansville, Indiana, United States, 47713
      • Boehringer Ingelheim Investigational Site
  • Kansas
    • Shawnee, Kansas, United States, 66216
      • Boehringer Ingelheim Investigational Site
    • Wichita, Kansas, United States, 67212
      • Boehringer Ingelheim Investigational Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70119
      • Boehringer Ingelheim Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Boehringer Ingelheim Investigational Site
    • Baltimore, Maryland, United States, 21218
      • 200
  • Missouri
    • Kansas City, Missouri, United States, 64114
      • Boehringer Ingelheim Investigational Site
    • St.Louis, Missouri, United States, 63141
      • 12401
  • Montana
    • Missoula, Montana, United States, 59802
      • Boehringer Ingelheim Investigational Site
  • New York
    • Brooklyn, New York, United States, 11203
      • Boehringer Ingelheim Investigational Site
    • Buffalo, New York, United States, 14209
      • 3
  • North Carolina
    • Berlin, North Carolina, United States, 08009
      • Comprehensive Clinical Research
    • Winston Salem, North Carolina, United States, 27103
      • Boehringer Ingelheim Investigational Site
  • Ohio
    • Kettering, Ohio, United States, 45429
      • Boehringer Ingelheim Investigational Site
    • Marion, Ohio, United States, 43302
      • Boehringer Ingelheim Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73132-4904
      • Boehringer Ingelheim Investigational Site
  • Oregon
    • Portland, Oregon, United States, 97232
      • Boehringer Ingelheim Investigational Site
  • Pennsylvania
    • Broomal, Pennsylvania, United States, 19008
      • Boehringer Ingelheim Investigational Site
  • Tennessee
    • Bartlett, Tennessee, United States, 38134
      • 6605
    • Fayetteville, Tennessee, United States, 37334
      • 108
  • Texas
    • Carrollton, Texas, United States, 75006
      • Boehringer Ingelheim Investigational Site
    • Dallas, Texas, United States, 75230
      • 7777
    • El Paso, Texas, United States, 79912
      • Boehringer Ingelheim Investigational Site
    • Harker Heights, Texas, United States, 76548
      • Team Research of Texas
    • San Antonio, Texas, United States, 78217
      • Boehringer Ingelheim Investigational Site
    • San Antonio, Texas, United States, 78229-4801
      • Boehringer Ingelheim Investigational Site
  • Utah
    • Salt Lake City, Utah, United States, 84111
      • 420
  • Virginia
    • Ettrick, Virginia, United States, 23803
      • 20901
  • Washington
    • Spokane, Washington, United States, 99207
      • Boehringer Ingelheim Investigational Site
  • Wisconsin
    • Miwaukee, Wisconsin, United States, 53295
      • 5000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 300 mg/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.
28. Any surgery that is, at the time of screening, planned to take place during the study period.
29. History of non-compliance with prescribed medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes from baseline in the mean SBP and DBP as measured by ambulatory blood pressure monitoring (ABPM)	10 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim Study Coordinator, B.I. Canada Ltd.

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2003
• Primary Completion (Actual): December 1, 2004
• Study Completion: December 1, 2004

Study Registration Dates

• First Submitted: October 14, 2005
• First Submitted That Met QC Criteria: October 14, 2005
• First Posted (Estimate): October 17, 2005

Study Record Updates

• Last Update Posted (Estimate): November 8, 2013
• Last Update Submitted That Met QC Criteria: November 7, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Valsartan; Hydrochlorothiazide; Telmisartan
• Other Study ID Numbers: 502.399