SMOOTH - Blood Pressure Control in Diabetic/Obese Patients

Hypertension Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00239538
• Other study ID #: 502.399
• Status: Completed
• Phase: Phase 4
• First received: October 14, 2005
• Last updated: November 7, 2013
• Start date: January 2003
• Est. completion date: December 2004

Study information

• Verified date: November 2013
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Therapeutic Products DirectorateU.S.A.: Food & Drug AdministrationMexico: Federal Commission for the Protection against Sanitary RiskArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaSouth Korea: Korea Food and Drug Administration (KFDA)Taiwan: Department of HealthAustralia/New Zealand: Therapeutic Goods Administration/New Zealand Medicines and Medical Devices Safety Authority
• Study type: Interventional

Clinical Trial 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

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 840
• Est. completion date: December 2004
• Est. primary completion date: December 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Hypertension

Intervention

Drug:
• telmisartan combined with hydrochlorothiazide (80/12.5 mg)

• valsartan combined with hydrochlorothiazide (160/12.5mg)

Locations

Country	Name	City	State
Argentina	Boehringer Ingelheim Investigational Site	BsAs
Argentina	Boehringer Ingelheim Investigational Site	Coronel Suárez
Argentina	Boehringer Ingelheim Investigational Site	Rosario, Sta. Fe
Australia	Boehringer Ingelheim Investigational Site	Kippa-Ring	Queensland
Australia	Emeritus Research	Malvern	Victoria
Australia	Boehringer Ingelheim Investigational Site	Prahran	Victoria
Canada	Boehringer Ingelheim Investigational Site	Bay Roberts	Newfoundland and Labrador
Canada	91 Thomas-Chapais	Boucherville	Quebec
Canada	Boehringer Ingelheim Investigational Site	Calgary	Alberta
Canada	Boehringer Ingelheim Investigational Site	Conquitlam	British Columbia
Canada	Boehringer Ingelheim Investigational Site	Halifax	Nova Scotia
Canada	Boehringer Ingelheim Investigational Site	Hamilton	Ontario
Canada	Boehringer Ingelheim Investigational Site	Kitchener	Ontario
Canada	Boehringer Ingelheim Investigational Site	London	Ontario
Canada	Boehringer Ingelheim Investigational Site	London	Ontario
Canada	Boehringer Ingelheim Investigational Site	Mississauga	Ontario
Canada	Boehringer Ingelheim Investigational Site	Montreal	Quebec
Canada	Boehringer Ingelheim Investigational Site	Mount Pearl	Newfoundland and Labrador
Canada	Boehringer Ingelheim Investigational Site	North York	Ontario
Canada	Boehringer Ingelheim Investigational Site	Oakville	Ontario
Canada	Boehringer Ingelheim Investigational Site	Orleans	Ontario
Canada	Pavillon St. Sacrement	Sainte-Foy	Quebec
Canada	Boehringer Ingelheim Investigational Site	Sarnia	Ontario
Canada	Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan
Canada	Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan
Canada	c/o Hemodynamics Offices	Saskatoon	Saskatchewan
Canada	LMC Thornhill	Thornhill	Ontario
Canada	Boehringer Ingelheim Investigational Site	Thunder Bay	Ontario
Canada	Boehringer Ingelheim Investigational Site	Toronto	Ontario
Canada	Boehringer Ingelheim Investigational Site	Vancouver	British Columbia
Canada	Dr. Hugh Tildesley	Vancouver	British Columbia
Korea, Republic of	Inje University Pusan Hospital	Busan
Korea, Republic of	Yeungnam University Medical Center	Daegu
Korea, Republic of	Korea University Medical Center	Seoul
Mexico	Boehringer Ingelheim Investigational Site	Col. Del Valle
Mexico	Boehringer Ingelheim Investigational Site	Col. Magdalena de las Salinas
Mexico	Boehringer Ingelheim Investigational Site	Col. Sección 16, México, D.F.
Mexico	Boehringer Ingelheim Investigational Site	Guadalajara, Jalisco
Mexico	Boehringer Ingelheim Investigational Site	Zapopan, Jalisco
New Zealand	Boehringer Ingelheim Investigational Site	Auckland
New Zealand	1st Floor Hagely Hostel	Christchurch
Taiwan	National Taiwan University Hospital	Taipei
United States	200	Baltimore	Maryland
United States	Boehringer Ingelheim Investigational Site	Baltimore	Maryland
United States	6605	Bartlett	Tennessee
United States	Comprehensive Clinical Research	Berlin	North Carolina
United States	Boehringer Ingelheim Investigational Site	Birmingham	Alabama
United States	Cooper Green Hospital	Birmingham	Alabama
United States	Boehringer Ingelheim Investigational Site	Brooklyn	New York
United States	Boehringer Ingelheim Investigational Site	Broomal	Pennsylvania
United States	3	Buffalo	New York
United States	Boehringer Ingelheim Investigational Site	Carrollton	Texas
United States	Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	Herron Medical Center, Ltd.	Chicago	Illinois
United States	7777	Dallas	Texas
United States	Boehringer Ingelheim Investigational Site	El Paso	Texas
United States	20901	Ettrick	Virginia
United States	Boehringer Ingelheim Investigational Site	Evansville	Indiana
United States	Boehringer Ingelheim Investigational Site	Evansville	Indiana
United States	108	Fayetteville	Tennessee
United States	Boehringer Ingelheim Investigational Site	Fort Lauderdale	Florida
United States	Boehringer Ingelheim Investigational Site	Ft. Lauderdale	Florida
United States	Boehringer Ingelheim Investigational Site	Glendale	Arizona
United States	Team Research of Texas	Harker Heights	Texas
United States	6448	Hollywood	Florida
United States	Boehringer Ingelheim Investigational Site	Huntsville	Alabama
United States	Boehringer Ingelheim Investigational Site	Kansas City	Missouri
United States	Boehringer Ingelheim Investigational Site	Kettering	Ohio
United States	Memorial Research Medical Clinic	Long Beach	California
United States	1200	Los Angeles	California
United States	Boehringer Ingelheim Investigational Site	Los Angeles	California
United States	Boehringer Ingelheim Investigational Site	Marion	Ohio
United States	Boehringer Ingelheim Investigational Site	Melbourne	Florida
United States	Boehringer Ingelheim Investigational Site	Missoula	Montana
United States	5000	Miwaukee	Wisconsin
United States	Boehringer Ingelheim Investigational Site	Mobile	Alabama
United States	Boehringer Ingelheim Investigational Site	New Orleans	Louisiana
United States	8615	Nuena Park	California
United States	Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma
United States	Boehringer Ingelheim Investigational Site	Orange	California
United States	Boehringer Ingelheim Investigational Site	Orland Park	Illinois
United States	Attention: Larry I. Gilderman, D.O.	Pembroke Pines	Florida
United States	Boehringer Ingelheim Investigational Site	Pembroke Pines	Florida
United States	Boehringer Ingelheim Investigational Site	Pembroke Pines	Florida
United States	Boehringer Ingelheim Investigational Site	Pinellas Park	Florida
United States	Boehringer Ingelheim Investigational Site	Portland	Oregon
United States	Boehringer Ingelheim Investigational Site	Sacramento	California
United States	Boehringer Ingelheim Investigational Site	Sacramento	California
United States	420	Salt Lake City	Utah
United States	Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	595	San Francisco	California
United States	Boehringer Ingelheim Investigational Site	Shawnee	Kansas
United States	Boehringer Ingelheim Investigational Site	Spokane	Washington
United States	12401	St.Louis	Missouri
United States	1805	Stockton	California
United States	Boehringer Ingelheim Investigational Site	Torrance	California
United States	Boehringer Ingelheim Investigational Site	Tucson	Arizona
United States	2311	Washington	District of Columbia
United States	Boehringer Ingelheim Investigational Site	West Palm Beach	Florida
United States	Boehringer Ingelheim Investigational Site	Wichita	Kansas
United States	Boehringer Ingelheim Investigational Site	Winston Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  Korea, Republic of,  Mexico,  New Zealand,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes from baseline in the mean SBP and DBP as measured by ambulatory blood pressure monitoring (ABPM)		10 weeks	No
Secondary	Changes from baseline in the last 6-hour ABPM mean (relative to dose time) pulse pressure.		10 weeks	No
Secondary	Changes from baseline in the 24-hour ABPM mean (relative to dose time) for SBP, DBP and pulse pressure.		10 weeks	No
Secondary	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	No
Secondary	Changes from baseline in SBP and DBP load during the 24-hour dosing interval.		10 weeks	No
Secondary	Responder rates based on the 24-hour ABPM mean (relative to dose time) blood pressures defined		10 weeks	No
Secondary	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	No
Secondary	Responder rates based on the mean seated trough cuff measurements		4 weeks and 10 weeks	No
Secondary	Metabolic and inflammatory marker changes from baseline		up to 10 weeks	No

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