Hypertension
Conditions
Keywords
Aliskiren, Amlodipine, Hypertension, SPA1000, Norvasc
Brief summary
This study will compare the safety and efficacy of initial combination treatment with aliskiren + amlodipine to sequential add-on treatment strategies with aliskiren or amlodipine in patients with hypertension.
Detailed description
This study was designed to evaluate if patients with hypertension treated early with a combination therapy would achieve better blood pressure (BP) control, than patients being treated with a classical sequential add-on therapy. The study compared the effects of the two treatment strategies: Treatment initiation on a single compound, either with aliskiren or amlodipine, and then continuation with the combination of both versus treatment initiation with the combination of aliskiren/amlodipine and then continuation with the combination. The study also evaluated if the overall mean sitting systolic blood pressure (msSBP)-lowering effect during the study, as well as the change from baseline to study end in msSBP, are superior in the group having received combination therapy from the beginning. The study further evaluated the BP-lowering efficacy and tolerability of both treatment strategies.
Interventions
DRUGAmlodipine
Amlodipine (5 mg and 10 mg) was provided as capsules taken orally once daily.
DRUGhydrochlorothiazide
Hydrochlorothiazide 12.5 mg capsules were taken orally once daily
DRUGAliskiren
Aliskiren 150 mg and aliskiren 300 mg were provided as film-coated tablets, taken orally once daily.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female outpatients ≥ 18 years of age * Participants with essential hypertension: * Naive participants must have a mean sitting Systolic Blood Pressure (msSBP) ≥ 150 mmHg and \< 180 mmHg at Visit 1 and Visit 2. (Participants are considered 'naïve' if they have never been treated with any antihypertensive medication.) * All participants must have a msSBP ≥ 150 mmHg and \< 180 mmHg at Visit 2 * Written informed consent to participate in this study prior to any study procedures
Exclusion criteria
* Severe hypertension * Pregnant or nursing (lactating) women * Pre-menopausal women not taking accepted form of birth control * Serum potassium ≥ 5.5 mEq/L (mmol/L) at Visit 1 * History of cardiovascular conditions * Uncontrolled Type 1 or Type 2 diabetes mellitus * Hypersensitivity to renin inhibitors, calcium channel blockers, or to drugs with similar chemical structures Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Mean Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Over 8, 16 and 24 Weeks | Baseline, 8 weeks, 16 weeks, and 24 weeks | Systolic Blood Pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and over 8, 16 and 24 weeks of study treatment. The overall mean change in msSBP from baseline was estimated over three time points: Week 8, Week 16, and Week 24. Analysis used a repeated measures Analysis of Covariance (ANCOVA) model with treatment, visit, and region as factors, treatment by visit interaction and baseline msSBP as a covariate. |
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 24 | Baseline to 24 weeks | Systolic Blood pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and 24 weeks of study treatment. Analysis used a repeated measures ANCOVA model with treatment, visit and region as factors, treatment by visit interaction and baseline msSBP as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 32 | Baseline to 32 weeks | Diastolic Blood Pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and 32 weeks of study treatment. Change at Week 32 used a separate repeated measures ANCOVA model containing Week 8, 16, 24 and 32 data. Treatment, visit and region were factors in the model, treatment by visit interaction and baseline msDBP a covariate. |
| Overall Mean Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) Over 8, 16, and 24 Weeks | Baseline, 8 weeks, 16 weeks and 24 weeks | Diastolic Blood pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and over 8, 16 and 24 weeks of study treatment. The overall mean change in msDBP from baseline was estimated over three time points: Week 8, Week 16, and Week 24. Analysis used a repeated measures ANCOVA model with treatment, visit and regions as factors, treatment by visit interaction and baseline msDBP as a covariate. |
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 24 | Baseline to 24 weeks | Diastolic Blood pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and 24 weeks of study treatment. Analysis used a repeated measures ANCOVA model with treatment, visit and region, as factors, treatment by visit interaction and baseline msDBP as a covariate. |
| Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Baseline to week 8, 16, 24 and 32 endpoints | Systolic & Diastolic Blood Pressure were measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and after 8, 16 , 24 and 32 weeks. Outcome is reported as percentage of participants achieving overall blood pressure control (msSBP \<140 mmHg and msDBP \<90 mmHg) at weeks 8, 16, 24 & 32 endpoints. |
Countries
Canada, Costa Rica, France, Germany, Greece, Guatemala, South Africa, Switzerland, United Kingdom, Venezuela
Participant flow
Pre-assignment details
A 2-4 week single-blind placebo run in. 7 patients were assigned a randomization number in error (3 each in the aliskiren/amlodipine initial treatment and aliskiren based add-on regimens and 1 in the amlodipine based add-on regimen). These patients did not take any double-blind study medication and were excluded from the Full Analysis Set (FAS).
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren+Amlodipine Eligible participants received oral aliskiren 150 mg + amlodipine 5 mg daily from week 1-8. From week 8 - 16, the dose of the combination treatment increased to aliskiren 300 mg + amlodipine 10 mg daily. From week 16-24, participants in this group continued combination treatment (aliskiren 300 mg + amlodipine 10 mg) for 8 weeks. At week 24, if blood pressure was not adequately controlled (systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg) hydrochlorothiazide 12.5 mg was added to the combination (aliskiren 300 mg + amlodipine 10 mg) for an additional 8 weeks. Total treatment period =32 weeks. | 620 |
| Aliskiren Start-Amlodipine Add On Eligible participants received oral aliskiren 150 mg daily from week 1-8. From week 8 - 16, the dose of aliskiren increased to 300 mg daily. From week 16-24, amlodipine 10 mg was added to the aliskiren 300 mg for 8 weeks (aliskiren 300 mg + amlodipine 10 mg). At week 24, if blood pressure was not adequately controlled (systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg) hydrochlorothiazide 12.5 mg was added to the combination (aliskiren 300 mg + amlodipine 10 mg) for an additional 8 weeks. Total treatment period =32 weeks. | 318 |
| Amlodipine Start-Aliskiren Add On Eligible participants received oral amlodipine 5 mg daily from week 1-8. From week 8 - 16, the dose of amlodipine increased to 10 mg daily. From week 16-24, aliskiren 300 mg was added to the amlodipine 10 mg for 8 weeks (amlodipine 10 mg + aliskiren 300 mg). At week 24, if blood pressure was not adequately controlled (systolic blood pressure \> 140 mmHg or diastolic blood pressure \>90 mmHg) hydrochlorothiazide 12.5 mg was added to the combination (amlodipine 10 mg + aliskiren 300 mg) for an additional 8 weeks. Total treatment period =32 weeks. | 316 |
| Total | 1,254 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal Test Procedure Result | 0 | 1 | 1 |
| Overall Study | Administrative Problem | 4 | 0 | 0 |
| Overall Study | Adverse Event | 86 | 44 | 58 |
| Overall Study | Lack of Efficacy | 1 | 7 | 6 |
| Overall Study | Lost to Follow-up | 11 | 0 | 5 |
| Overall Study | Mis-randomized | 3 | 3 | 1 |
| Overall Study | No longer required study medication | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 4 | 6 | 8 |
| Overall Study | Withdrawal by Subject | 14 | 7 | 7 |
Baseline characteristics
| Characteristic | Aliskiren+Amlodipine | Aliskiren Start-Amlodipine Add On | Amlodipine Start-Aliskiren Add On | Total |
|---|---|---|---|---|
| Age Continuous | 58.1 years STANDARD_DEVIATION 10.81 | 58.4 years STANDARD_DEVIATION 10.83 | 58.1 years STANDARD_DEVIATION 10.93 | 58.1 years STANDARD_DEVIATION 10.84 |
| Sex: Female, Male Female | 305 Participants | 154 Participants | 160 Participants | 619 Participants |
| Sex: Female, Male Male | 315 Participants | 164 Participants | 156 Participants | 635 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 196 / 617 | 81 / 315 | 104 / 315 |
| serious Total, serious adverse events | 14 / 617 | 9 / 315 | 9 / 315 |
Outcome results
Primary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 24
Systolic Blood pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and 24 weeks of study treatment. Analysis used a repeated measures ANCOVA model with treatment, visit and region as factors, treatment by visit interaction and baseline msSBP as a covariate.
Time frame: Baseline to 24 weeks
Population: The analysis population included participants in the Full Analysis Set, (randomized participants who received at least one dose of study drug) for whom efficacy data was available for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren+Amlodipine | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 24 | -27.37 mmHg | Standard Error 0.546 |
| Aliskiren Start-Amlodipine Add On | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 24 | -26.34 mmHg | Standard Error 0.738 |
| Amlodipine Start-Aliskiren Add On | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 24 | -25.52 mmHg | Standard Error 0.782 |
Primary
Overall Mean Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Over 8, 16 and 24 Weeks
Systolic Blood Pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and over 8, 16 and 24 weeks of study treatment. The overall mean change in msSBP from baseline was estimated over three time points: Week 8, Week 16, and Week 24. Analysis used a repeated measures Analysis of Covariance (ANCOVA) model with treatment, visit, and region as factors, treatment by visit interaction and baseline msSBP as a covariate.
Time frame: Baseline, 8 weeks, 16 weeks, and 24 weeks
Population: The analysis population included participants in the Full Analysis Set, (randomized participants who received at least one dose of study drug) for whom efficacy data was available for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren+Amlodipine | Overall Mean Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Over 8, 16 and 24 Weeks | -25.34 mmHg | Standard Error 0.436 |
| Aliskiren Start-Amlodipine Add On | Overall Mean Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Over 8, 16 and 24 Weeks | -17.94 mmHg | Standard Error 0.6 |
| Amlodipine Start-Aliskiren Add On | Overall Mean Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Over 8, 16 and 24 Weeks | -19.81 mmHg | Standard Error 0.611 |
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 24
Diastolic Blood pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and 24 weeks of study treatment. Analysis used a repeated measures ANCOVA model with treatment, visit and region, as factors, treatment by visit interaction and baseline msDBP as a covariate.
Time frame: Baseline to 24 weeks
Population: The analysis population included participants in the Full Analysis Set, (randomized participants who received at least one dose of study drug) for whom efficacy data was available for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren+Amlodipine | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 24 | -13.64 mmHg | Standard Error 0.319 |
| Aliskiren Start-Amlodipine Add On | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 24 | -13.22 mmHg | Standard Error 0.431 |
| Amlodipine Start-Aliskiren Add On | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 24 | -12.25 mmHg | Standard Error 0.457 |
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 32
Diastolic Blood Pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and 32 weeks of study treatment. Change at Week 32 used a separate repeated measures ANCOVA model containing Week 8, 16, 24 and 32 data. Treatment, visit and region were factors in the model, treatment by visit interaction and baseline msDBP a covariate.
Time frame: Baseline to 32 weeks
Population: The analysis population included participants in the Full Analysis Set, (randomized participants who received at least one dose of study drug) for whom efficacy data was available for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren+Amlodipine | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 32 | -12.96 mmHg | Standard Error 0.323 |
| Aliskiren Start-Amlodipine Add On | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 32 | -12.96 mmHg | Standard Error 0.446 |
| Amlodipine Start-Aliskiren Add On | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 32 | -11.62 mmHg | Standard Error 0.467 |
Secondary
Overall Mean Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) Over 8, 16, and 24 Weeks
Diastolic Blood pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and over 8, 16 and 24 weeks of study treatment. The overall mean change in msDBP from baseline was estimated over three time points: Week 8, Week 16, and Week 24. Analysis used a repeated measures ANCOVA model with treatment, visit and regions as factors, treatment by visit interaction and baseline msDBP as a covariate.
Time frame: Baseline, 8 weeks, 16 weeks and 24 weeks
Population: The analysis population included participants in the Full Analysis Set, (randomized participants who received at least one dose of study drug) for whom efficacy data was available for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren+Amlodipine | Overall Mean Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) Over 8, 16, and 24 Weeks | -12.39 mmHg | Standard Error 0.247 |
| Aliskiren Start-Amlodipine Add On | Overall Mean Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) Over 8, 16, and 24 Weeks | -8.37 mmHg | Standard Error 0.34 |
| Amlodipine Start-Aliskiren Add On | Overall Mean Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) Over 8, 16, and 24 Weeks | -9.02 mmHg | Standard Error 0.347 |
Secondary
Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints
Systolic & Diastolic Blood Pressure were measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and after 8, 16 , 24 and 32 weeks. Outcome is reported as percentage of participants achieving overall blood pressure control (msSBP \<140 mmHg and msDBP \<90 mmHg) at weeks 8, 16, 24 & 32 endpoints.
Time frame: Baseline to week 8, 16, 24 and 32 endpoints
Population: The analysis population included participants in the Full Analysis Set, (randomized participants who received at least one dose of study drug) for whom efficacy data was available for this outcome measure. Last post-baseline observation was carried forward to each visit for the analysis of blood pressure control.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Aliskiren+Amlodipine | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 8 endpoint | 46.5 Percentage of Participants | 0.566 |
| Aliskiren+Amlodipine | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 24 endpoint | 63.4 Percentage of Participants | — |
| Aliskiren+Amlodipine | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 16 endpoint | 65.9 Percentage of Participants | — |
| Aliskiren+Amlodipine | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 32 endpoint | 61.6 Percentage of Participants | — |
| Aliskiren Start-Amlodipine Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 32 endpoint | 59.0 Percentage of Participants | — |
| Aliskiren Start-Amlodipine Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 16 endpoint | 33.3 Percentage of Participants | — |
| Aliskiren Start-Amlodipine Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 8 endpoint | 22.8 Percentage of Participants | 0.781 |
| Aliskiren Start-Amlodipine Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 24 endpoint | 62.8 Percentage of Participants | — |
| Amlodipine Start-Aliskiren Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 16 endpoint | 40.9 Percentage of Participants | — |
| Amlodipine Start-Aliskiren Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 8 endpoint | 25.2 Percentage of Participants | 0.816 |
| Amlodipine Start-Aliskiren Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 32 endpoint | 53.4 Percentage of Participants | — |
| Amlodipine Start-Aliskiren Add On | Percentage of Participants Achieving Overall Blood Pressure Control at 8, 16, 24 and 32 Weeks Endpoints | Week 24 endpoint | 57.8 Percentage of Participants | — |
Post Hoc
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 32
Systolic Blood pressure was measured in a sitting position using a validated automated blood pressure monitor (the Omron device) according to Guidelines of the British Hypertension Society, at Baseline and 32 weeks of study treatment. Change at week 32 used a separate repeated measures ANCOVA model containing Week 8, 16, 24 & 32 data. Treatment, visit and region were factors in the model, treatment by visit interaction and baseline msSBP was a covariate.
Time frame: Baseline to 32 weeks
Population: The analysis population included participants in the Full Analysis Set, (randomized participants who received at least one dose of study drug) for whom efficacy data was available for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren+Amlodipine | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 32 | -26.42 mmHg | Standard Error 0.566 |
| Aliskiren Start-Amlodipine Add On | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 32 | -25.75 mmHg | Standard Error 0.781 |
| Amlodipine Start-Aliskiren Add On | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 32 | -24.32 mmHg | Standard Error 0.816 |