Hypertension
Conditions
Keywords
aliskiren, antihypertensive, hypertension, renin inhibitor, moderate-severe hypertension
Brief summary
This study evaluated the efficacy (blood pressure lowering effect) and safety of aliskiren/amlodipine/hydrochlorothiazide in patients with moderate to severe hypertension.
Interventions
DRUGAliskiren
150 and 300 mg tablets
DRUGAmlodipine
5 and 10 mg capsules
12.5 and 25 mg capsules
DRUGPlacebo
tablet
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female * 18 years of age or older * msDBP and msSBP requirements: * 3A: * Diagnosis of moderate to severe hypertension (msSBP ≥ 160 mmHg and \< 200 mmHg, and/or msDBP ≥ 100 mmHg and \< 120 mmHg) at Visits 4, 5 or 6 (Qualifying BP visit) * In addition, at the visit immediately prior to the above qualifying visit, patients were also to have msSBP ≥ 145 mmHg and \< 200 mmHg and msDBP ≥ 95 mmHg and \< 120 mmHg) at Visits 3, 5 or 5. * Patients had to meet the above two sets of requirements at subsequent adjacent visits, i.e. either Visits 3 and 4, Visits 4 and 5, or Visits 5 and 6. * OR * 3B: * msSBP ≥ 180 mmHg and \< 200 mmHg with msDBP ≥ 95 mmHg and \< 120 mmHg, or msDBP ≥ 110 mmHg and \< 120 mmHg with msSBP ≥ 150 mmHg and \< 200 mmHg after at least one week of treatment with placebo (Visit 3 and on).
Exclusion criteria
* Continued use of anti-hypertensive medicines or use of 4 or more hypertensive medicines at study start * Patients with an msSBP ≥ 200 mmHg or msDBP ≥ 120 mmHg at any time during the placebo run-in period were to be discontinued from the study. * Extremely elevated (defined) blood pressure at any point during the study * Pregnant or lactating women * Pre-menopausal women not taking accepted form of birth control * History or evidence of secondary form of hypertension * History of cardiovascular conditions Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8) | Baseline to end of study (Week 8) | Blood pressure (BP) was measured at trough (24±3 hours post-dose). The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. If there was \< 0.5 mmHg difference in BP between the 2 arms, the non-dominant arm was used. At each visit, after the patient was in a sitting position with the back supported and both feet placed on the floor for 5 minutes, systolic and diastolic BP were measured 3 times with an automated BP monitor and appropriate size cuff. Means of the 3 measurements were calculated. A negative change indicates lowered BP. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8) | Baseline to end of study (Week 8) | Blood pressure (BP) was measured at trough (24±3 hours post-dose). The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. If there was \< 0.5 mmHg difference in BP between the 2 arms, the non-dominant arm was used. At each visit, after the patient was in a sitting position with the back supported and both feet placed on the floor for 5 minutes, systolic and diastolic BP were measured 3 times with an automated BP monitor and appropriate size cuff. Means of the 3 measurements were calculated. A negative change indicates lowered BP. |
| Percentage of Patients Achieving Blood Pressure Control at the End of the Study (Week 8) | End of study (Week 8) | Blood pressure control was defined as a msSBP/msDBP \< 140/90 mmHg at the end of the study (Week 8). Blood pressure (BP) was measured at trough (24±3 hours post-dose). The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position with the back supported and both feet placed on the floor for 5 minutes, systolic and diastolic BP were measured 3 times with an automated BP monitor and appropriate size cuff. Means of the 3 measurements were calculated. |
| Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Baseline to end of study (Week 8) | Twenty-four hour ambulatory blood pressure monitoring (ABPM) was performed in a subset of patients twice during the study, once at baseline and again at Week 8. The ABPM device was placed on the non-dominant arm between 7:00 and 10:00 am and verification readings obtained. If they were successful, the investigator initiated the 24 hour reading and instructed the patient regarding ABPM procedures. On the next day, the ABPM device was removed if it had been worn for a minimum of 24 hours. The ABPM data were downloaded and evaluated on site. |
Countries
Australia, Canada, Denmark, Germany, Israel, Italy, Latvia, Lithuania, Romania, Sweden, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
In the single-blind period, 1909 patients were enrolled, 1189 completed, and 720 discontinued. Of the 1191 randomized patients, 2 patients were randomized by error and discontinued in the single-blind period without taking double-blind medication.
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren / Amlodipine Patients received an aliskiren 150 mg tablet plus an amlodipine 5 mg capsule for 4 weeks and then were force titrated up to aliskiren 300 mg plus amlodipine 10 mg for the remaining 4 weeks of the study. During the 8 weeks, patients also received a placebo tablet and a placebo capsule. Patients took a total of 4 pills each day orally with water in the morning at approximately 8:00 am, except on the morning of a study visit when they took their study medications after all visit procedures and assessments had been completed. | 287 |
| Aliskiren / Hydrochlorothiazide Patients received an aliskiren 150 mg tablet plus a hydrochlorothiazide 12.5 mg capsule for 4 weeks and then were force titrated up to aliskiren 300 mg plus hydrochlorothiazide 25 mg for the remaining 4 weeks of the study. During the 8 weeks, patients also received a placebo capsule and a placebo tablet. Patients took a total of 4 pills each day orally with water in the morning at approximately 8:00 am, except on the morning of a study visit when they took their study medications after all visit procedures and assessments had been completed. | 298 |
| Amlodipine / Hydrochlorothiazide Patients received an amlodipine 5 mg capsule plus a hydrochlorothiazide 12.5 mg capsule for 4 weeks and then were force titrated up to amlodipine 10 mg plus hydrochlorothiazide 25 mg for the remaining 4 weeks of the study. During the 8 weeks, patients also received 2 placebo tablets. Patients took a total of 4 pills each day orally with water in the morning at approximately 8:00 am, except on the morning of a study visit when they took their study medications after all visit procedures and assessments had been completed | 296 |
| Aliskiren / Amlodipine / Hydrochlorothiazide Patients received an aliskiren 150 mg tablet, a HCTZ 12.5 mg capsule and a placebo capsule for the first 3 days of treatment. Amlodipine 5 mg was then added for the remainder of the first 4 weeks of treatment. At the end of 4 weeks, patients were force titrated up to aliskiren / amlodipine / hydrochlorothiazide 300/10/25 mg for the remaining 4 weeks of the study. During the 8 weeks, patients also received a placebo tablet. Patients took a total of 4 pills each day orally with water in the morning at approximately 8:00 am, except on the morning of a study visit when they took their study medications after all visit procedures and assessments had been completed | 310 |
| Total | 1,191 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Abnormal Laboratory Value(s) | 0 | 0 | 1 | 0 |
| Overall Study | Abnormal Test Procedure Result(s) | 1 | 3 | 1 | 2 |
| Overall Study | Adverse Event | 7 | 2 | 8 | 11 |
| Overall Study | Lack of Efficacy | 2 | 3 | 1 | 2 |
| Overall Study | Lost to Follow-up | 4 | 6 | 2 | 1 |
| Overall Study | Protocol Violation | 2 | 0 | 1 | 0 |
| Overall Study | Randomized in Error - No Study Drug | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 7 | 3 | 8 |
Baseline characteristics
| Characteristic | Aliskiren / Amlodipine | Aliskiren / Hydrochlorothiazide | Amlodipine / Hydrochlorothiazide | Aliskiren / Amlodipine / Hydrochlorothiazide | Total |
|---|---|---|---|---|---|
| Age Continuous | 54.4 years STANDARD_DEVIATION 11.33 | 55.5 years STANDARD_DEVIATION 10.75 | 55.1 years STANDARD_DEVIATION 10.86 | 55.4 years STANDARD_DEVIATION 10.54 | 55.1 years STANDARD_DEVIATION 10.86 |
| Age, Customized < 65 years | 237 participants | 242 participants | 233 participants | 251 participants | 963 participants |
| Age, Customized >=65 years | 50 participants | 56 participants | 63 participants | 59 participants | 228 participants |
| Sex: Female, Male Female | 115 Participants | 123 Participants | 110 Participants | 123 Participants | 471 Participants |
| Sex: Female, Male Male | 172 Participants | 175 Participants | 186 Participants | 187 Participants | 720 Participants |
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 | 32 / 287 | 17 / 297 | 26 / 295 | 29 / 309 |
| serious Total, serious adverse events | 3 / 287 | 2 / 297 | 2 / 295 | 6 / 309 |
Outcome results
Primary
Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8)
Blood pressure (BP) was measured at trough (24±3 hours post-dose). The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. If there was \< 0.5 mmHg difference in BP between the 2 arms, the non-dominant arm was used. At each visit, after the patient was in a sitting position with the back supported and both feet placed on the floor for 5 minutes, systolic and diastolic BP were measured 3 times with an automated BP monitor and appropriate size cuff. Means of the 3 measurements were calculated. A negative change indicates lowered BP.
Time frame: Baseline to end of study (Week 8)
Population: Full analysis set population: All randomized patients who had post-baseline efficacy measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren / Amlodipine | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8) | -31.37 mmHg | Standard Error 0.9 |
| Aliskiren / Hydrochlorothiazide | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8) | -27.99 mmHg | Standard Error 0.88 |
| Amlodipine / Hydrochlorothiazide | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8) | -30.77 mmHg | Standard Error 0.88 |
| Aliskiren / Amlodipine / Hydrochlorothiazide | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8) | -37.92 mmHg | Standard Error 0.86 |
Secondary
Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8)
Twenty-four hour ambulatory blood pressure monitoring (ABPM) was performed in a subset of patients twice during the study, once at baseline and again at Week 8. The ABPM device was placed on the non-dominant arm between 7:00 and 10:00 am and verification readings obtained. If they were successful, the investigator initiated the 24 hour reading and instructed the patient regarding ABPM procedures. On the next day, the ABPM device was removed if it had been worn for a minimum of 24 hours. The ABPM data were downloaded and evaluated on site.
Time frame: Baseline to end of study (Week 8)
Population: Full analysis set population: All randomized patients who had post-baseline efficacy measurements.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren / Amlodipine | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Systolic BP | -20.30 mmHg | Standard Error 0.52 |
| Aliskiren / Amlodipine | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Diastolic BP | -13.29 mmHg | Standard Error 0.36 |
| Aliskiren / Hydrochlorothiazide | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Diastolic BP | -9.57 mmHg | Standard Error 0.35 |
| Aliskiren / Hydrochlorothiazide | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Systolic BP | -16.27 mmHg | Standard Error 0.51 |
| Amlodipine / Hydrochlorothiazide | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Systolic BP | -18.67 mmHg | Standard Error 0.53 |
| Amlodipine / Hydrochlorothiazide | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Diastolic BP | -11.20 mmHg | Standard Error 0.37 |
| Aliskiren / Amlodipine / Hydrochlorothiazide | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Systolic BP | -25.29 mmHg | Standard Error 0.51 |
| Aliskiren / Amlodipine / Hydrochlorothiazide | Change in Mean 24-hour Ambulatory Systolic and Diastolic Blood Pressure From Baseline to End of Study (Week 8) | Diastolic BP | -15.90 mmHg | Standard Error 0.35 |
Secondary
Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8)
Blood pressure (BP) was measured at trough (24±3 hours post-dose). The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. If there was \< 0.5 mmHg difference in BP between the 2 arms, the non-dominant arm was used. At each visit, after the patient was in a sitting position with the back supported and both feet placed on the floor for 5 minutes, systolic and diastolic BP were measured 3 times with an automated BP monitor and appropriate size cuff. Means of the 3 measurements were calculated. A negative change indicates lowered BP.
Time frame: Baseline to end of study (Week 8)
Population: Full analysis set population: All randomized patients who had post-baseline efficacy measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren / Amlodipine | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8) | -18.03 mmHg | Standard Error 0.57 |
| Aliskiren / Hydrochlorothiazide | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8) | -14.32 mmHg | Standard Error 0.55 |
| Amlodipine / Hydrochlorothiazide | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8) | -17.03 mmHg | Standard Error 0.55 |
| Aliskiren / Amlodipine / Hydrochlorothiazide | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8) | -20.63 mmHg | Standard Error 0.54 |
Secondary
Percentage of Patients Achieving Blood Pressure Control at the End of the Study (Week 8)
Blood pressure control was defined as a msSBP/msDBP \< 140/90 mmHg at the end of the study (Week 8). Blood pressure (BP) was measured at trough (24±3 hours post-dose). The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position with the back supported and both feet placed on the floor for 5 minutes, systolic and diastolic BP were measured 3 times with an automated BP monitor and appropriate size cuff. Means of the 3 measurements were calculated.
Time frame: End of study (Week 8)
Population: Full analysis set population: All randomized patients who had post-baseline efficacy measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren / Amlodipine | Percentage of Patients Achieving Blood Pressure Control at the End of the Study (Week 8) | 41.3 Percentage of patients |
| Aliskiren / Hydrochlorothiazide | Percentage of Patients Achieving Blood Pressure Control at the End of the Study (Week 8) | 33.1 Percentage of patients |
| Amlodipine / Hydrochlorothiazide | Percentage of Patients Achieving Blood Pressure Control at the End of the Study (Week 8) | 39.0 Percentage of patients |
| Aliskiren / Amlodipine / Hydrochlorothiazide | Percentage of Patients Achieving Blood Pressure Control at the End of the Study (Week 8) | 62.3 Percentage of patients |