Essential Hypertension
Conditions
Keywords
Essential hypertension, High blood pressure
Brief summary
This study will assess whether LCZ696 when used in combination with amlodipine will provide greater BP lowering benefit compared to amlodipine alone in Asian hypertensive patients not adequately responsive to amlodipine therapy.
Interventions
DRUGLCZ696
LCZ696 will use tablets available at a strength of 200mg. Patients will be instructed to take the prescribed medication once a day.
DRUGAmlodipine
Amlodipine will use tablets available at a strength of 5 mg. Patients will be instructed to take the prescribed medication once a day.
DRUGPlacebo
Matching placebo to LCZ696
Sponsors
Novartis Pharmaceuticals
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
Patients must give written informed consent and have a diagnosis of hypertension: Untreated patients must have an msSBP ≥ 150 mmHg and \< 180 mmHg at both Visit 1 and Visit 101. Pre-treated patients must have an msSBP ≥ 145 mmHg and \< 180 mmHg after wash out at Visit 101. All patients must have an office msSBP ≥ 145 mmHg and \< 180 mmHg at the completion of the 4-week run-in epoch (at the randomization visit (Visit 201). Patients must successfully complete ABPM and pass technical requirements at Visit 201.
Exclusion criteria
Malignant or severe hypertension (grade 3 of WHO classification; msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg). History of angioedema, drug-related or otherwise. History or evidence of a secondary form of hypertension. Transient ischemic cerebral attack (TIA) during the 12 months prior to Visit 1 or any history of stroke. History of myocardial infarction, coronary bypass surgery or PCI during the 12 months prior to Visit 1 Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean 24-hour Ambulatory Blood Pressure Monitoring (ABPM) Systolic Blood Pressure (maSBP) | 8 weeks | The change in mean 24 hour ambulatory systolic blood pressure (maSBP) from baseline to end of the study (week 8) in the 2 groups was measured. A greater reduction from baseline in the LCZ696 group indicates a positive treatment effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Sitting Systolic Blood Pressure (msSBP) | 8 weeks | The change in the patient's msSBP from baseline to end of the study was measured. A reduction from baseline indicates a positive treatment effect. |
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) | 8 weeks | The change in the patient's msDBP from baseline to end of the study was measured. A reduction from baseline indicates a positive treatment effect. |
| Change in Sitting Pulse Pressure (PP) | 8 weeks | The change in the patient's mean sitting PP from baseline to end of the study was measured. Pulse pressure measures the difference in mean sitting systolic blood pressure and mean sitting diastolic blood pressure. |
| Change in Mean 24-hour ABPM Diastolic Blood Pressure (maDBP) | 8 weeks | The change in mean 24 hour maDBP from baseline to end of the study was measured. A reduction from baseline indicates a positive treatment effect. |
| Number of Participants Achieving Successful Response in msSBP (< 140 mmHg or a Reduction ≥ 20 mmHg From Baseline) | 8 weeks | The number of participants who achieved successful treatment response in the msSBP of \< 140mmHg or a reduction ≥ 20 mmHg from baseline after completing study treatment was measured. Participants who achieved either of the above targets were deemed as a having a successful response. |
| Number of Participants Achieving Successful Response in msDBP (< 90 mmHg or a Reduction ≥ 10 mmHg From Baseline) | 8 weeks of treatment | The number of participants who achieved successful treatment response in msDBP of \< 90mmHg or a reduction ≥ 10mmHg from baseline after completing study treatment was measured. Participants who achieved either of the above targets were deemed as having a successful response. |
| Number of Participants With Adverse Event | 8 weeks | Participants were monitored for adverse events, serious adverse events and death. |
| Number of Participants Achieving Systolic and Diastolic Blood Pressure Control (< 140/90 mmHg) | 8 weeks | The number of participants achieving a systolic and diastolic blood pressure \< 140/90 mmHg was measured. This outcome measure shows how well a given blood pressure treatment can achieve a given blood pressure target or goal. Participants who achieved the target blood pressure were determined based on the mean SBP and DBP measurements taken at the end of the study. If the participants' BP measurement was below the above target, they were considered to have successful blood pressure control. |
Countries
China, Japan, Malaysia, Philippines, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 and Amlodipine Participants, first treated with 5 mg of amlodipine for 4 weeks to determine if they were not adequately responding to amlodipine (an office msSBP ≥145 mmHg and \<180 mmHg) and who met all inclusion and exclusion criteria), were randomized to receive 200mg of LCZ696 in combination with 5 mg of amlodipine for 8 weeks. | 130 |
| Amlodipine Participants, first treated with 5 mg of amlodipine for 4 weeks to determine if they were not adequately responding to amlodipine (an office msSBP ≥145 mmHg and \<180 mmHg) and who met all inclusion and exclusion criteria), were randomized to receive 5 mg of amlodipine and placebo to LCZ696 for 8 weeks. | 136 |
| Total | 266 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Deviation | 1 | 4 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | LCZ696 and Amlodipine | Amlodipine | Total |
|---|---|---|---|
| Age, Continuous | 55.4 Years STANDARD_DEVIATION 9.31 | 55.5 Years STANDARD_DEVIATION 9.43 | 55.4 Years STANDARD_DEVIATION 9.35 |
| Sex: Female, Male Female | 49 Participants | 61 Participants | 110 Participants |
| Sex: Female, Male Male | 81 Participants | 75 Participants | 156 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 130 | 19 / 136 |
| serious Total, serious adverse events | 0 / 130 | 0 / 136 |
Outcome results
Primary
Change in Mean 24-hour Ambulatory Blood Pressure Monitoring (ABPM) Systolic Blood Pressure (maSBP)
The change in mean 24 hour ambulatory systolic blood pressure (maSBP) from baseline to end of the study (week 8) in the 2 groups was measured. A greater reduction from baseline in the LCZ696 group indicates a positive treatment effect.
Time frame: 8 weeks
Population: FAS: This set included all randomized participants who received at least one dose of study medication. Among the 266 Full Analysis Set (FAS) participants, 251 participants (123 participants in the LCZ696 + amlodipine group and 128 participants in the amlodipine group) had eligible ABPM at both baseline and endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 and Amlodipine | Change in Mean 24-hour Ambulatory Blood Pressure Monitoring (ABPM) Systolic Blood Pressure (maSBP) | -13.93 mmHg | Standard Error 0.56 |
| Amlodipine | Change in Mean 24-hour Ambulatory Blood Pressure Monitoring (ABPM) Systolic Blood Pressure (maSBP) | -0.82 mmHg | Standard Error 0.56 |
Secondary
Change in Mean 24-hour ABPM Diastolic Blood Pressure (maDBP)
The change in mean 24 hour maDBP from baseline to end of the study was measured. A reduction from baseline indicates a positive treatment effect.
Time frame: 8 weeks
Population: FAS: This set included all randomized participants who received at least one dose of study medication. Among the 266 Full Analysis Set (FAS) participants, 251 participants (123 participants in the LCZ696 + amlodipine group and 128 participants in the amlodipine group) had eligible ABPM at both baseline and endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 and Amlodipine | Change in Mean 24-hour ABPM Diastolic Blood Pressure (maDBP) | -8.03 mmHg | Standard Error 0.38 |
| Amlodipine | Change in Mean 24-hour ABPM Diastolic Blood Pressure (maDBP) | -0.33 mmHg | Standard Error 0.37 |
Secondary
Change in Mean Sitting Diastolic Blood Pressure (msDBP)
The change in the patient's msDBP from baseline to end of the study was measured. A reduction from baseline indicates a positive treatment effect.
Time frame: 8 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 and Amlodipine | Change in Mean Sitting Diastolic Blood Pressure (msDBP) | -9.22 mmHg | Standard Error 0.83 |
| Amlodipine | Change in Mean Sitting Diastolic Blood Pressure (msDBP) | -3.96 mmHg | Standard Error 0.82 |
Secondary
Change in Mean Sitting Systolic Blood Pressure (msSBP)
The change in the patient's msSBP from baseline to end of the study was measured. A reduction from baseline indicates a positive treatment effect.
Time frame: 8 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 and Amlodipine | Change in Mean Sitting Systolic Blood Pressure (msSBP) | -19.60 mmHg | Standard Error 1.35 |
| Amlodipine | Change in Mean Sitting Systolic Blood Pressure (msSBP) | -9.34 mmHg | Standard Error 1.33 |
Secondary
Change in Sitting Pulse Pressure (PP)
The change in the patient's mean sitting PP from baseline to end of the study was measured. Pulse pressure measures the difference in mean sitting systolic blood pressure and mean sitting diastolic blood pressure.
Time frame: 8 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 and Amlodipine | Change in Sitting Pulse Pressure (PP) | -10.31 mmHg | Standard Error 0.9 |
| Amlodipine | Change in Sitting Pulse Pressure (PP) | -5.46 mmHg | Standard Error 0.89 |
Secondary
Number of Participants Achieving Successful Response in msDBP (< 90 mmHg or a Reduction ≥ 10 mmHg From Baseline)
The number of participants who achieved successful treatment response in msDBP of \< 90mmHg or a reduction ≥ 10mmHg from baseline after completing study treatment was measured. Participants who achieved either of the above targets were deemed as having a successful response.
Time frame: 8 weeks of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 and Amlodipine | Number of Participants Achieving Successful Response in msDBP (< 90 mmHg or a Reduction ≥ 10 mmHg From Baseline) | 112 Participants |
| Amlodipine | Number of Participants Achieving Successful Response in msDBP (< 90 mmHg or a Reduction ≥ 10 mmHg From Baseline) | 95 Participants |
Secondary
Number of Participants Achieving Successful Response in msSBP (< 140 mmHg or a Reduction ≥ 20 mmHg From Baseline)
The number of participants who achieved successful treatment response in the msSBP of \< 140mmHg or a reduction ≥ 20 mmHg from baseline after completing study treatment was measured. Participants who achieved either of the above targets were deemed as a having a successful response.
Time frame: 8 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 and Amlodipine | Number of Participants Achieving Successful Response in msSBP (< 140 mmHg or a Reduction ≥ 20 mmHg From Baseline) | 98 Participants |
| Amlodipine | Number of Participants Achieving Successful Response in msSBP (< 140 mmHg or a Reduction ≥ 20 mmHg From Baseline) | 53 Participants |
Secondary
Number of Participants Achieving Systolic and Diastolic Blood Pressure Control (< 140/90 mmHg)
The number of participants achieving a systolic and diastolic blood pressure \< 140/90 mmHg was measured. This outcome measure shows how well a given blood pressure treatment can achieve a given blood pressure target or goal. Participants who achieved the target blood pressure were determined based on the mean SBP and DBP measurements taken at the end of the study. If the participants' BP measurement was below the above target, they were considered to have successful blood pressure control.
Time frame: 8 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 and Amlodipine | Number of Participants Achieving Systolic and Diastolic Blood Pressure Control (< 140/90 mmHg) | 89 Participants |
| Amlodipine | Number of Participants Achieving Systolic and Diastolic Blood Pressure Control (< 140/90 mmHg) | 46 Participants |
Secondary
Number of Participants With Adverse Event
Participants were monitored for adverse events, serious adverse events and death.
Time frame: 8 weeks
Population: Safety Set: The safety set included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 and Amlodipine | Number of Participants With Adverse Event | Adverse Events (serious and non-serious) | 26 Participants |
| LCZ696 and Amlodipine | Number of Participants With Adverse Event | Serious Adverse Events | 0 Participants |
| LCZ696 and Amlodipine | Number of Participants With Adverse Event | Deaths | 0 Participants |
| Amlodipine | Number of Participants With Adverse Event | Adverse Events (serious and non-serious) | 29 Participants |
| Amlodipine | Number of Participants With Adverse Event | Serious Adverse Events | 0 Participants |
| Amlodipine | Number of Participants With Adverse Event | Deaths | 0 Participants |