Essential Hypertension
Conditions
Keywords
Aliskiren, Amlodipine, Essential hypertension
Brief summary
The purpose of the study was to evaluate the efficacy (blood pressure lowering effect) and safety of SPA100 (Fixed-dose Combination of Aliskiren and Amlodipine) in patients with essential hypertension (mean sitting diastolic blood pressure \[msDBP\] ≥ 95 mmHg and \< 110 mmHg and mean sitting systolic blood pressure \[msSBP\] ≥ 140 mmHg ). This study was conducted to support registration of the fixed-dose combination of aliskiren and amlodipine for the treatment of hypertension in Japan.
Interventions
DRUGAliskiren/Amlodipine 150/2.5 mg
Aliskiren/amlodipine 150/2.5 mg tablet
DRUGAliskiren/amlodipine 150/5 mg
Aliskiren/amlodipine 150/5 mg tablet
DRUGAliskiren 150 mg
Aliskiren 150 mg tablet
Amlodipine 2.5 mg capsule
Aliskiren placebo tablet
Amlodipine placebo capsule
DRUGPlacebo of Aliskiren/amlodipine 150/2.5 mg
Aliskiren/amlodipine 150/2.5 mg placebo tablet
DRUGPlacebo of Aliskiren/amlodipine 150/5 mg
Aliskiren/amlodipine 150/5 mg placebo tablet
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with essential hypertension (msDBP ≥ 95 mmHg and \< 110 mmHg and msSBP ≥140 mmHg ) * Outpatients
Exclusion criteria
* Severe hypertension (msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg) * History of allergy or hypersensitivity to renin inhibitors, calcium channel blockers * History or evidence of a secondary hypertension Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8) | Baseline, Week 8 | Sitting blood pressure was measured at trough (24 hours ± 2 hours post dose) and recorded at all study visits. At the first study visit, blood pressure was measured in both arms and the arm with highest sitting DBP was found and used for all subsequent readings throughout the study. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these three sitting blood pressure measurements were used as the average sitting blood pressure for that visit. Analysis of covariance (ANCOVA) model contained treatment and region as two factors and baseline as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8) | Baseline, Week 8 | Sitting blood pressure was measured at trough (24 hours ± 2 hours post dose) and recorded at all study visits. At the first study visit, blood pressure was measured in both arms and the arm with highest sitting DBP was found and used for all subsequent readings throughout the study. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these three sitting blood pressure measurements were used as the average sitting blood pressure for that visit. Analysis of covariance (ANCOVA) model contained treatment and region as two factors and baseline as a covariate. |
| Percentage of Participants Achieving Blood Pressure Control at Endpoint | 8 weeks | Blood pressure control is defined as having as a msDBP \< 90 mmHg and a msSBP \< 140 mmHg. |
| Percentage of Participants Achieving a Successful Response Rate | 8 weeks | The response rate was defined as percentage of participants who achieved msDBP \< 90 mmHg or its reduction ≥ 10 mmHg from baseline to endpoint. |
| Number of Participants With Adverse Events, Serious Adverse Events and Death | 8 weeks | Number of patients with adverse events regardless of study drug relationship during the double-blind treatment period were reported. Serious adverse events of double blind period were reported. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo In order to adequately blind the study, patients were required to take a total of 3 tablets and 2 capsules of study medication throughout the study. Patients were received matching placebo of aliskiren/amlodipine 150/5 mg tablet, aliskiren/amlodipine 150/2.5 mg tablet, aliskiren 150 mg tablet and two amlodipine 2.5 mg capsules once daily for 8 weeks of double blind period. | 153 |
| Aliskiren 150 mg In order to adequately blind the study, patients were required to take a total of 3 tablets and 2 capsules of study medication throughout the study.
Patients received Aliskiren 150 mg tablet once daily (o.d)+ placebo of two amlodipine 2.5 mg capsule o.d., aliskiren/amlodipine 150/5 mg tablet o.d , aliskiren/amlodipine 150/2.5 mg tablet o.d for 8 weeks of double blind period. | 157 |
| Amlodipine 2.5 mg In order to adequately blind the study, patients were required to take a total of 3 tablets and 2 capsules of study medication throughout the study.
Patients received Amlodipine 2.5 mg capsule once daily (o.d)+ placebo of amlodipine 2.5 mg capsule o.d., Aliskiren 150 mg o.d., aliskiren/amlodipine 150/5 mg tablet o.d , aliskiren/amlodipine 150/2.5 mg tablet o.d for 8 weeks of double blind period. | 158 |
| Amlodipine 5 mg In order to adequately blind the study, patients were required to take a total of 3 tablets and 2 capsules of study medication throughout the study.
Patients received amlodipine 5 mg (two amlodipine 2.5 mg capsules o.d.)+ placebo of aliskiren 150 mg tablet o.d., aliskiren/amlodipine 150/5 mg tablet o.d. , aliskiren/amlodipine 150/2.5 mg tablet o.d. for 8 weeks of double blind period. | 158 |
| Aliskiren/Amlodipine 150/2.5 mg In order to adequately blind the study, patients were required to take a total of 3 tablets and 2 capsules of study medication throughout the study.
Patients received aliskiren/amlodipine 150/2.5 mg tablet o.d. + placebo of two amlodipine 2.5 mg capsules o.d., aliskiren 150 mg tablet o.d., aliskiren/amlodipine 150/5 mg tablet o.d. for 8 weeks of double blind period. | 159 |
| Aliskiren/Amlodipine 150/5 mg In order to adequately blind the study, patients were required to take a total of 3 tablets and 2 capsules of study medication throughout the study.
Patients received aliskiren/amlodipine 150/5 mg tablet o.d. + placebo of two amlodipine 2.5 mg capsules o.d., aliskiren 150 mg tablet o.d., aliskiren/amlodipine 150/2.5 mg tablet o.d. for 8 weeks of double blind period. | 159 |
| Total | 944 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double Blind (Treatment Period, 8 Weeks) | Administrative problems | 0 | 0 | 0 | 0 | 0 | 1 |
| Double Blind (Treatment Period, 8 Weeks) | Adverse Event | 12 | 4 | 3 | 2 | 2 | 1 |
| Double Blind (Treatment Period, 8 Weeks) | Protocol deviation(s) | 0 | 1 | 1 | 2 | 1 | 1 |
| Double Blind (Treatment Period, 8 Weeks) | Unsatisfactory therapeutic effect | 20 | 6 | 7 | 1 | 0 | 1 |
| Double Blind (Treatment Period, 8 Weeks) | Withdrawal by Subject | 1 | 4 | 4 | 0 | 1 | 1 |
| Single Blind(Run-in Period, 4 Weeks) | Abnormal laboratory value(s) | 25 | 0 | 0 | 0 | 0 | 0 |
| Single Blind(Run-in Period, 4 Weeks) | Abnormal test procedure result(s) | 308 | 0 | 0 | 0 | 0 | 0 |
| Single Blind(Run-in Period, 4 Weeks) | Adverse Event | 29 | 0 | 0 | 0 | 0 | 0 |
| Single Blind(Run-in Period, 4 Weeks) | Protocol deviation(s) | 8 | 0 | 0 | 0 | 0 | 0 |
| Single Blind(Run-in Period, 4 Weeks) | Subject withdrew consent | 28 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Aliskiren 150 mg | Amlodipine 2.5 mg | Amlodipine 5 mg | Aliskiren/Amlodipine 150/2.5 mg | Aliskiren/Amlodipine 150/5 mg | Total |
|---|---|---|---|---|---|---|---|
| Age Continuous | 54.6 years STANDARD_DEVIATION 8.35 | 55.0 years STANDARD_DEVIATION 9.96 | 54.8 years STANDARD_DEVIATION 10.25 | 55.8 years STANDARD_DEVIATION 10.05 | 54.6 years STANDARD_DEVIATION 11.11 | 55.5 years STANDARD_DEVIATION 9.86 | 55.1 years STANDARD_DEVIATION 9.96 |
| Age, Customized < 65 years | 128 participants | 131 participants | 129 participants | 126 participants | 125 participants | 127 participants | 766 participants |
| Age, Customized >=65 years | 25 participants | 26 participants | 29 participants | 32 participants | 34 participants | 32 participants | 178 participants |
| Sex: Female, Male Female | 45 Participants | 39 Participants | 45 Participants | 51 Participants | 51 Participants | 57 Participants | 288 Participants |
| Sex: Female, Male Male | 108 Participants | 118 Participants | 113 Participants | 107 Participants | 108 Participants | 102 Participants | 656 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 153 | 21 / 157 | 17 / 158 | 21 / 158 | 17 / 159 | 19 / 159 | 136 / 1,342 |
| serious Total, serious adverse events | 0 / 153 | 0 / 157 | 2 / 158 | 1 / 158 | 0 / 159 | 1 / 159 | 4 / 1,342 |
Outcome results
Primary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8)
Sitting blood pressure was measured at trough (24 hours ± 2 hours post dose) and recorded at all study visits. At the first study visit, blood pressure was measured in both arms and the arm with highest sitting DBP was found and used for all subsequent readings throughout the study. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these three sitting blood pressure measurements were used as the average sitting blood pressure for that visit. Analysis of covariance (ANCOVA) model contained treatment and region as two factors and baseline as a covariate.
Time frame: Baseline, Week 8
Population: Full analysis set (FAS): All randomized patients received at least one dose of double-blind study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8) | -5.21 mm Hg | Standard Error 0.69 |
| Aliskiren 150 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8) | -7.49 mm Hg | Standard Error 0.68 |
| Amlodipine 2.5 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8) | -9.46 mm Hg | Standard Error 0.68 |
| Amlodipine 5 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8) | -11.90 mm Hg | Standard Error 0.68 |
| Aliskiren/Amlodipine 150/2.5 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8) | -12.40 mm Hg | Standard Error 0.68 |
| Aliskiren/Amlodipine 150/5 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) to End of Study (Week 8) | -16.43 mm Hg | Standard Error 0.68 |
Secondary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8)
Sitting blood pressure was measured at trough (24 hours ± 2 hours post dose) and recorded at all study visits. At the first study visit, blood pressure was measured in both arms and the arm with highest sitting DBP was found and used for all subsequent readings throughout the study. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these three sitting blood pressure measurements were used as the average sitting blood pressure for that visit. Analysis of covariance (ANCOVA) model contained treatment and region as two factors and baseline as a covariate.
Time frame: Baseline, Week 8
Population: Full analysis set (FAS): All randomized patients received at least one dose of double-blind study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8) | -4.57 mm Hg | Standard Error 0.97 |
| Aliskiren 150 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8) | -10.63 mm Hg | Standard Error 0.96 |
| Amlodipine 2.5 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8) | -13.16 mm Hg | Standard Error 0.96 |
| Amlodipine 5 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8) | -17.98 mm Hg | Standard Error 0.96 |
| Aliskiren/Amlodipine 150/2.5 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8) | -18.15 mm Hg | Standard Error 0.96 |
| Aliskiren/Amlodipine 150/5 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) to End of Study (Week 8) | -25.49 mm Hg | Standard Error 0.96 |
Secondary
Number of Participants With Adverse Events, Serious Adverse Events and Death
Number of patients with adverse events regardless of study drug relationship during the double-blind treatment period were reported. Serious adverse events of double blind period were reported.
Time frame: 8 weeks
Population: Safety set: All patients who received at least one dose of double-blind study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 0 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse Events | 62 Participants |
| Aliskiren 150 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 0 Participants |
| Aliskiren 150 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse Events | 57 Participants |
| Aliskiren 150 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Amlodipine 2.5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 2 Participants |
| Amlodipine 2.5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse Events | 50 Participants |
| Amlodipine 2.5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Amlodipine 5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 1 Participants |
| Amlodipine 5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse Events | 49 Participants |
| Amlodipine 5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Aliskiren/Amlodipine 150/2.5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse Events | 57 Participants |
| Aliskiren/Amlodipine 150/2.5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 0 Participants |
| Aliskiren/Amlodipine 150/2.5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Aliskiren/Amlodipine 150/5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse Events | 59 Participants |
| Aliskiren/Amlodipine 150/5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Aliskiren/Amlodipine 150/5 mg | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 1 Participants |
Secondary
Percentage of Participants Achieving a Successful Response Rate
The response rate was defined as percentage of participants who achieved msDBP \< 90 mmHg or its reduction ≥ 10 mmHg from baseline to endpoint.
Time frame: 8 weeks
Population: Full analysis set (FAS) included all randomized patients received at least one dose of double-blind study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving a Successful Response Rate | 34.6 percentage of participants |
| Aliskiren 150 mg | Percentage of Participants Achieving a Successful Response Rate | 46.5 percentage of participants |
| Amlodipine 2.5 mg | Percentage of Participants Achieving a Successful Response Rate | 50.6 percentage of participants |
| Amlodipine 5 mg | Percentage of Participants Achieving a Successful Response Rate | 70.3 percentage of participants |
| Aliskiren/Amlodipine 150/2.5 mg | Percentage of Participants Achieving a Successful Response Rate | 65.4 percentage of participants |
| Aliskiren/Amlodipine 150/5 mg | Percentage of Participants Achieving a Successful Response Rate | 86.2 percentage of participants |
Secondary
Percentage of Participants Achieving Blood Pressure Control at Endpoint
Blood pressure control is defined as having as a msDBP \< 90 mmHg and a msSBP \< 140 mmHg.
Time frame: 8 weeks
Population: Full analysis set (FAS) included all randomized patients received at least one dose of double-blind study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving Blood Pressure Control at Endpoint | 16.3 percentage of participants |
| Aliskiren 150 mg | Percentage of Participants Achieving Blood Pressure Control at Endpoint | 25.5 percentage of participants |
| Amlodipine 2.5 mg | Percentage of Participants Achieving Blood Pressure Control at Endpoint | 32.9 percentage of participants |
| Amlodipine 5 mg | Percentage of Participants Achieving Blood Pressure Control at Endpoint | 50.0 percentage of participants |
| Aliskiren/Amlodipine 150/2.5 mg | Percentage of Participants Achieving Blood Pressure Control at Endpoint | 45.9 percentage of participants |
| Aliskiren/Amlodipine 150/5 mg | Percentage of Participants Achieving Blood Pressure Control at Endpoint | 69.2 percentage of participants |