Clinical trial NCT00239538: SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2005-10-17
Enrollment: 840
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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)

Eligibility criteria: 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.

Primary outcomes:
measure: Changes from baseline in the mean SBP and DBP as measured by ambulatory blood pressure monitoring (ABPM)
timeFrame: 10 weeks
Secondary outcomes:
measure: Changes from baseline in the last 6-hour ABPM mean (relative to dose time) pulse pressure.
timeFrame: 10 weeks
measure: Changes from baseline in the 24-hour ABPM mean (relative to dose time) for SBP, DBP and pulse pressure.
timeFrame: 10 weeks
measure: 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.
timeFrame: 10 weeks
measure: Changes from baseline in SBP and DBP load during the 24-hour dosing interval.
timeFrame: 10 weeks
measure: Responder rates based on the 24-hour ABPM mean (relative to dose time) blood pressures defined
timeFrame: 10 weeks
measure: 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.
timeFrame: 4 weeks and 10 weeks
measure: Responder rates based on the mean seated trough cuff measurements
timeFrame: 4 weeks and 10 weeks
measure: Metabolic and inflammatory marker changes from baseline
timeFrame: up to 10 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Cooper Green Hospital
state: Alabama
city: Birmingham
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Alabama
city: Huntsville
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Alabama
city: Mobile
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Alabama
city: Glendale
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Arizona
city: Tucson
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Arizona
city: Long Beach
country: United States
facility: Memorial Research Medical Clinic
state: California
city: Los Angeles
country: United States
facility: 1200
state: California
city: Los Angeles
country: United States
facility: Boehringer Ingelheim Investigational Site
state: California
city: Nuena Park
country: United States
facility: 8615
state: California
city: Orange
country: United States
facility: Boehringer Ingelheim Investigational Site
state: California
city: Sacramento
country: United States
facility: Boehringer Ingelheim Investigational Site
state: California
city: Sacramento
country: United States
facility: Boehringer Ingelheim Investigational Site
state: California
city: San Francisco
country: United States
facility: 595
state: California
city: Stockton
country: United States
facility: 1805
state: California
city: Torrance
country: United States
facility: Boehringer Ingelheim Investigational Site
state: California
city: Washington
country: United States
facility: 2311
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Florida
city: Ft. Lauderdale
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Florida
city: Hollywood
country: United States
facility: 6448
state: Florida
city: Melbourne
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: Attention: Larry I. Gilderman, D.O.
state: Florida
city: Pembroke Pines
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Florida
city: Pinellas Park
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Florida
city: West Palm Beach
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Florida
city: Chicago
country: United States
facility: Herron Medical Center, Ltd.
state: Illinois
city: Chicago
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Illinois
city: Orland Park
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Illinois
city: Evansville
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Indiana
city: Evansville
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Indiana
city: Shawnee
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Kansas
city: Wichita
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Kansas
city: New Orleans
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Louisiana
city: Baltimore
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Maryland
city: Baltimore
country: United States
facility: 200
state: Maryland
city: Kansas City
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Missouri
city: St.Louis
country: United States
facility: 12401
state: Missouri
city: Missoula
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Montana
city: Brooklyn
country: United States
facility: Boehringer Ingelheim Investigational Site
state: New York
city: Buffalo
country: United States
facility: 3
state: New York
city: Berlin
country: United States
facility: Comprehensive Clinical Research
state: North Carolina
city: Winston Salem
country: United States
facility: Boehringer Ingelheim Investigational Site
state: North Carolina
city: Kettering
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Ohio
city: Marion
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Oklahoma
city: Portland
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Oregon
city: Broomal
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Pennsylvania
city: Bartlett
country: United States
facility: 6605
state: Tennessee
city: Fayetteville
country: United States
facility: 108
state: Tennessee
city: Carrollton
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Texas
city: Dallas
country: United States
facility: 7777
state: Texas
city: El Paso
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Texas
city: Harker Heights
country: United States
facility: Team Research of Texas
state: Texas
city: San Antonio
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Texas
city: San Antonio
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: 420
state: Utah
city: Ettrick
country: United States
facility: 20901
state: Virginia
city: Spokane
country: United States
facility: Boehringer Ingelheim Investigational Site
state: Washington
city: Miwaukee
country: United States
facility: 5000
state: Wisconsin
city: BsAs
country: Argentina
facility: Boehringer Ingelheim Investigational Site
city: Coronel Suárez
country: Argentina
facility: Boehringer Ingelheim Investigational Site
city: Rosario, Sta. Fe
country: Argentina
facility: Boehringer Ingelheim Investigational Site
city: Kippa-Ring
country: Australia
facility: Boehringer Ingelheim Investigational Site
state: Queensland
city: Malvern
country: Australia
facility: Emeritus Research
state: Victoria
city: Prahran
country: Australia
facility: Boehringer Ingelheim Investigational Site
state: Victoria
city: Calgary
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Alberta
city: Conquitlam
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: Dr. Hugh Tildesley
state: British Columbia
city: Vancouver
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: British Columbia
city: Bay Roberts
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Newfoundland and Labrador
city: Mount Pearl
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Nova Scotia
city: Hamilton
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Kitchener
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: London
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: London
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Mississauga
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: North York
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Oakville
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Orleans
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Thornhill
country: Canada
facility: LMC Thornhill
state: Ontario
city: Thunder Bay
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Ontario
city: Boucherville
country: Canada
facility: 91 Thomas-Chapais
state: Quebec
city: Montreal
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Quebec
city: Sainte-Foy
country: Canada
facility: Pavillon St. Sacrement
state: Quebec
city: Saskatoon
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Boehringer Ingelheim Investigational Site
state: Saskatchewan
city: Saskatoon
country: Canada
facility: c/o Hemodynamics Offices
state: Saskatchewan
city: Busan
country: Korea, Republic of
facility: Inje University Pusan Hospital
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Medical Center
city: Col. Del Valle
country: Mexico
facility: Boehringer Ingelheim Investigational Site
city: Col. Magdalena de las Salinas
country: Mexico
facility: Boehringer Ingelheim Investigational Site
city: Col. Sección 16, México, D.F.
country: Mexico
facility: Boehringer Ingelheim Investigational Site
city: Guadalajara, Jalisco
country: Mexico
facility: Boehringer Ingelheim Investigational Site
city: Zapopan, Jalisco
country: Mexico
facility: Boehringer Ingelheim Investigational Site
city: Auckland
country: New Zealand
facility: Boehringer Ingelheim Investigational Site
city: Christchurch
country: New Zealand
facility: 1st Floor Hagely Hostel
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: B.I. Canada Ltd.
name: Boehringer Ingelheim Study Coordinator
role: STUDY_CHAIR
References: