Hypertension
Conditions
Brief summary
To determine the effectiveness of four different strength combinations of three approved anti-hypertension therapies (olmesartan medoxomil, amlodipine, and hydrochlorothiazide) for lowering blood pressure.
Interventions
DRUGOlmesartan medoxomil
40mg olmesartan medoxomil
DRUGAmlodipine
Amlodipine 10mg
DRUGHydrochlorothiazide
Hydrochlorothiazide 25mg
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Demonstrable hypertension defined as mean sitting trough cuff blood pressure ≥ 140/100 mmHg (SeSBP ≥ 140 mmHg and SeDBP ≥ 100mmHg) or mean sitting trough cuff BP ≥ 160/90 mmHg (SeSBP ≥ 160 mmHg and SeDBP ≥ 90mmHg). * Male or female newly diagnosed hypertensive subjects or currently on hypertension medication. * Negative urine pregnancy test at screening * Not lactating * Do not plan to become pregnant during the study * Will practice birth control throughout the study by the following: oral or patch contraceptive, injectable or implantable contraceptive medication, intrauterine device, diaphragm or female condom plus spermicide * Non childbearing potential must be classified by one of the following criteria * Had a hysterectomy or tubal ligation at least 6 months prior to consent * Has been postmenopausal for a least 1 year
Exclusion criteria
* Mean sitting trough cuff DBP \<90 mmHg or mean sitting trough cuff SBP \<140 mmHg (off antihypertensive medication). * Subjects with uncontrolled hypertension taking multiple antihypertensive therapies (at the discretion of the investigator). * Signs or symptoms which could exacerbate the occurrence of hypotension such as volume and salt depletion. * History of hypertensive encephalopathy, stroke or transient ischemic attack (TIA). * Participation in another clinical trial involving an investigational drug within one month prior to screening. * History of myocardial infarction, percutaneous transluminal coronary revascularization, coronary artery bypass graft, and/or unstable angina within the past 6 months. * Any history of New York Heart Association Class III or IV congestive heart failure (CHF). A history of New York Heart Association Class I or II CHF may be exclusionary at the discretion of the investigator. * History of secondary hypertension including renal disease, pheochromocytoma, or Cushing's syndrome. * Uncorrected coarctation of the aorta, bilateral renal artery stenosis, or unilateral renal artery stenosis in a solitary kidney. * Evidence of symptomatic resting bradycardia. * Evidence of hemodynamically significant cardiac valvular disease. * Presence of heart block greater than first degree atrioventricular block, chronic atrial fibrillation or flutter. * Uncontrolled Type I or Type II diabetes defined as HbA1c \>9.0%. Diabetics must have documentation of HbA1c within 6 months of the Screening Visit. Undocumented subjects must have their HbA1c assessed prior to randomization. Note: Subjects with Type I or Type II diabetes controlled with insulin, diet or oral hypoglycemic agents on a stable dose for at least 30 days may be included. * Evidence of liver disease as indicated by ALT and AST and/or total bilirubin \>3 times the upper limit of normal. * Severe renal insufficiency defined as a creatinine clearance (based on the Cockcroft-Gault formula) of \<30 mL/min. * Clinically significant laboratory elevations at Visit 1 that compromise subject safety, based on the investigator's judgment. Consideration should take into account the potential laboratory effects of the component blinded therapies. * Positive for any one of the following tests: hepatitis B surface antigen, hepatitis C antibody (confirmed by radio immunobinding assay, RIBA) or HIV antibody (confirmed by western blot assay). * Subjects with malignancy during the past 2 years excluding squamous cell or basal cell carcinoma of the skin. * Known allergy to any of the medications used in the study. * Subjects who require or are taking any concomitant medication, which may interfere with the objectives of the study (Refer to Section 5.2 for a listing of excluded medications). * Pregnant or lactating females. * Current history of drug or alcohol abuse. * A subject with any medical condition, which in the judgment of the Investigator would jeopardize the evaluation of efficacy or safety and/or constitute a significant safety risk to the subject.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline to Week 12 in Seated Diastolic Blood Pressure (SeDBP). | baseline to 12 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Subjects Who Reached Blood Pressure Goal (<140/90 mmHg; <130/80 mmHg for Subjects With Diabetes, Chronic Renal Disease, or Chronic Cardiovascular Disease)by 12 Weeks | Baseline to 12 weeks |
| Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Baseline to 12 weeks or early termination |
| Change in Seated Systolic Blood Pressure From Baseline to Week 12 | Baseline to week 12 |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
First subject first visit 12 May 2008. Last subject last follow-up 27 Feb 2009. 317 sites in USA and Puerto Rico. Planned: 2400 subjects (600 per treatment arm). Enrolled: 6724 subjects. Randomized: 2492 subjects.
Pre-assignment details
Duration of the study was 57 weeks with 52 weeks of treatment. This included 3-week stabilization/washout (Period I), 12-week double blind treatment (Period II), 40 week open label treatment (Period III), and 2-week post treatment follow-up (Period IV).
Participants by arm
| Arm | Count |
|---|---|
| OM40/AML10 Double blind treatment olmesartan medoxomil (OM) 40 mg, Amlodipine (AML) 10 mg tablets once daily. | 628 |
| OM40/HCTZ25 Double blind treatment olmesartan medoxomil (OM) 40 mg, Hydrochlorothiazide (HCTZ) 25 mg tablets once daily. | 637 |
| AML10/HCTZ25 Double blind treatment Amlodipine (AML) 10 mg, Hydrochlorothiazide (HCTZ) 25 mg tablets once daily. | 600 |
| OM40/AML10/HCTZ25 Double blind treatment olmesartan medoxomil (OM) 40 mg, Amlodipine (AML) 10 mg, Hydrochlorothiazide (HCTZ) 25 mg, tablets once daily. | 627 |
| Total | 2,492 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 22 | 46 | 38 | 48 |
| Overall Study | Lost to Follow-up | 15 | 17 | 21 | 26 |
| Overall Study | Other | 3 | 9 | 1 | 6 |
| Overall Study | Protocol Violation | 11 | 13 | 9 | 8 |
| Overall Study | Withdrawal by Subject | 20 | 21 | 19 | 23 |
Baseline characteristics
| Characteristic | OM40/AML10 | OM40/HCTZ25 | AML10/HCTZ25 | OM40/AML10/HCTZ25 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 120 Participants | 132 Participants | 96 Participants | 123 Participants | 471 Participants |
| Age, Categorical Between 18 and 65 years | 508 Participants | 505 Participants | 504 Participants | 504 Participants | 2021 Participants |
| Age, Continuous | 55.1 years STANDARD_DEVIATION 10.93 | 55.9 years STANDARD_DEVIATION 10.78 | 54.6 years STANDARD_DEVIATION 10.82 | 54.7 years STANDARD_DEVIATION 11.22 | 55.1 years STANDARD_DEVIATION 10.94 |
| Body Mass Index Greater than or equal to 30 kg/m2 | 399 Participants | 399 Participants | 370 Participants | 387 Participants | 1555 Participants |
| Body Mass Index Less than 30 kg/m2 | 229 Participants | 238 Participants | 230 Participants | 240 Participants | 937 Participants |
| Diabetes Status Diabetic | 100 Participants | 99 Participants | 92 Participants | 96 Participants | 387 Participants |
| Diabetes Status Not diabetic | 528 Participants | 538 Participants | 508 Participants | 531 Participants | 2105 Participants |
| Duration of hypertension | 10.12 years STANDARD_DEVIATION 9.865 | 10.34 years STANDARD_DEVIATION 9.826 | 9.73 years STANDARD_DEVIATION 8.983 | 9.54 years STANDARD_DEVIATION 9.558 | 9.94 years STANDARD_DEVIATION 9.571 |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 3 Participants | 1 Participants | 4 Participants | 1 Participants | 9 Participants |
| Race/Ethnicity, Customized Asian | 13 Participants | 10 Participants | 7 Participants | 19 Participants | 49 Participants |
| Race/Ethnicity, Customized Black/African American | 181 Participants | 200 Participants | 192 Participants | 184 Participants | 757 Participants |
| Race/Ethnicity, Customized Hawaiian/Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 4 Participants | 5 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized White | 431 Participants | 421 Participants | 391 Participants | 415 Participants | 1658 Participants |
| Sex: Female, Male Female | 303 Participants | 298 Participants | 266 Participants | 307 Participants | 1174 Participants |
| Sex: Female, Male Male | 325 Participants | 339 Participants | 334 Participants | 320 Participants | 1318 Participants |
| Weight | 95.9 kg STANDARD_DEVIATION 22.65 | 96.1 kg STANDARD_DEVIATION 22.55 | 96.1 kg STANDARD_DEVIATION 23.41 | 96.0 kg STANDARD_DEVIATION 23.24 | 96.0 kg STANDARD_DEVIATION 22.94 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 210 / 596 | 210 / 580 | 212 / 552 | 237 / 574 |
| serious Total, serious adverse events | 9 / 596 | 7 / 580 | 9 / 552 | 10 / 574 |
Outcome results
Primary
Change From Baseline to Week 12 in Seated Diastolic Blood Pressure (SeDBP).
Time frame: baseline to 12 weeks
Population: The full analysis set consists of subjects who received at least 1 dose of study medication and had a baseline and at least one post-dose assessment of SeDBP
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OM40/AML10 | Change From Baseline to Week 12 in Seated Diastolic Blood Pressure (SeDBP). | -17.8 mm Hg | Standard Deviation 9.47 |
| OM40/HCTZ25 | Change From Baseline to Week 12 in Seated Diastolic Blood Pressure (SeDBP). | -16.5 mm Hg | Standard Deviation 10.84 |
| AML10/HCTZ25 | Change From Baseline to Week 12 in Seated Diastolic Blood Pressure (SeDBP). | -14.8 mm Hg | Standard Deviation 8.78 |
| OM40/AML10/HCTZ25 | Change From Baseline to Week 12 in Seated Diastolic Blood Pressure (SeDBP). | -21.5 mm Hg | Standard Deviation 10.25 |
Comparison: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Secondary
Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination
Time frame: Baseline to 12 weeks or early termination
Population: The ABPM Analysis Set included 440 subjects who provided consent to participate in the ABPM sub-study and who were to provide ABPM measurements prior to and after randomization. Those analyzed is the number who had values at both baseline and 12 weeks or early termination
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OM40/AML10 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Diastolic blood pressure | -13.9 mm Hg | Standard Deviation 8.09 |
| OM40/AML10 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Systolic blood pressure | -23.5 mm Hg | Standard Deviation 11.8 |
| OM40/HCTZ25 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Diastolic blood pressure | -14.5 mm Hg | Standard Deviation 8.73 |
| OM40/HCTZ25 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Systolic blood pressure | -23.9 mm Hg | Standard Deviation 13.1 |
| AML10/HCTZ25 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Diastolic blood pressure | -10.7 mm Hg | Standard Deviation 7.46 |
| AML10/HCTZ25 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Systolic blood pressure | -18.5 mm Hg | Standard Deviation 10.67 |
| OM40/AML10/HCTZ25 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Systolic blood pressure | -30.3 mm Hg | Standard Deviation 13.85 |
| OM40/AML10/HCTZ25 | Change in Mean 24-hour Ambulatory Blood Pressure From Baseline to Week 12 or Early Termination | Diastolic blood pressure | -18.0 mm Hg | Standard Deviation 8.11 |
Comparison: Diastolic blood pressure: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: Diastolic blood pressure: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: Diastolic blood pressure: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: 0.0001ANCOVA
Comparison: Systolic blood pressure: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: Systolic blood pressure: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: Systolic blood pressure: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Secondary
Change in Seated Systolic Blood Pressure From Baseline to Week 12
Time frame: Baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OM40/AML10 | Change in Seated Systolic Blood Pressure From Baseline to Week 12 | -31.1 mm Hg | Standard Deviation 15.44 |
| OM40/HCTZ25 | Change in Seated Systolic Blood Pressure From Baseline to Week 12 | -31.2 mm Hg | Standard Deviation 18.58 |
| AML10/HCTZ25 | Change in Seated Systolic Blood Pressure From Baseline to Week 12 | -28.9 mm Hg | Standard Deviation 15.12 |
| OM40/AML10/HCTZ25 | Change in Seated Systolic Blood Pressure From Baseline to Week 12 | -38.1 mm Hg | Standard Deviation 17.4 |
Comparison: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Comparison: All treatment comparisons were calculated as OM40/AML10/HCTZ25 minus the respective dual combination treatment group. Least-squares mean differences, SEs, and 2-sided p-values were obtained from an ANCOVA model with baseline blood pressure as a covariate, and fixed effects of treatment, age group, race group, and diabetic status.p-value: <0.0001ANCOVA
Secondary
Percentage of Subjects Who Reached Blood Pressure Goal (<140/90 mmHg; <130/80 mmHg for Subjects With Diabetes, Chronic Renal Disease, or Chronic Cardiovascular Disease)by 12 Weeks
Time frame: Baseline to 12 weeks
Population: The full analysis set consists of subjects who received at least 1 dose of study medication and had a baseline and at least one post-dose assessment of seated diastolic blood pressure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OM40/AML10 | Percentage of Subjects Who Reached Blood Pressure Goal (<140/90 mmHg; <130/80 mmHg for Subjects With Diabetes, Chronic Renal Disease, or Chronic Cardiovascular Disease)by 12 Weeks | 46.0 Percentage of subjects |
| OM40/HCTZ25 | Percentage of Subjects Who Reached Blood Pressure Goal (<140/90 mmHg; <130/80 mmHg for Subjects With Diabetes, Chronic Renal Disease, or Chronic Cardiovascular Disease)by 12 Weeks | 46.6 Percentage of subjects |
| AML10/HCTZ25 | Percentage of Subjects Who Reached Blood Pressure Goal (<140/90 mmHg; <130/80 mmHg for Subjects With Diabetes, Chronic Renal Disease, or Chronic Cardiovascular Disease)by 12 Weeks | 34.9 Percentage of subjects |
| OM40/AML10/HCTZ25 | Percentage of Subjects Who Reached Blood Pressure Goal (<140/90 mmHg; <130/80 mmHg for Subjects With Diabetes, Chronic Renal Disease, or Chronic Cardiovascular Disease)by 12 Weeks | 64.3 Percentage of subjects |
Comparison: Each p-value was obtained from individual Cochran-Mantel-Haenszel tests stratified by age group, race group, and diabetic status comparing the triple combination therapy to each dual combination.p-value: <0.0001Cochran-Mantel-Haenszel
Comparison: Each p-value was obtained from individual Cochran-Mantel-Haenszel tests stratified by age group, race group, and diabetic status comparing the triple combination therapy to each dual combination.p-value: <0.0001Cochran-Mantel-Haenszel
Comparison: Each p-value was obtained from individual Cochran-Mantel-Haenszel tests stratified by age group, race group, and diabetic status comparing the triple combination therapy to each dual combination.p-value: <0.0001Cochran-Mantel-Haenszel