Essential Hypertension
Conditions
Keywords
Essential hypertension, LCZ696
Brief summary
This study assessed the efficacy of LCZ696 in Japanese patients with essential hypertension
Interventions
DRUGLCZ696
200 mg (one tablet) or 400 mg (2 tablets of 200mg) once daily
DRUGOlmesartan
Olmesartan 20 mg capsule one daily
DRUGPlacebo
Placebo to LCZ696 or Olmesartan
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with mild-to-moderate hypertension, untreated or currently taking antihypertensive therapy. * Treated patients (using antihypertensive treatments within 4 weeks prior to Visit 1) must have an msSBP ≥ 150 mmHg and \< 180 mmHg at the randomization visit (Visit 201) and msSBP ≥140 mmHg \< 180 mmHg at the visit immediately proceeding Visit 201 (Visit 102 or 103). * Untreated patients (newly diagnosed with essential hypertension or having a history of hypertension but have not been taking any antihypertensive drugs for at least 4 weeks prior to Visit 1) must have an msSBP ≥ 150 mmHg and \< 180 mmHg at both Visit 1 and Visit 201. * Patients must have an absolute difference of ≤15 mmHg in msSBP between Visit 201 and the immediately preceding visit;
Exclusion criteria
* Severe hypertension (msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg). * History of angioedema, drug-related or otherwise, as reported by the patient. * History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension. * Patients who previously entered a LCZ696 study and had been randomized or enrolled into the active drug treatment epoch. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | Baseline, 8 weeks | Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurements. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | Baseline, 8 weeks | Sitting BP measurement was performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurement. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline. |
| Percentage of Participants Achieving a Successful Response in Overall Blood Pressure Control at Week 8 | 8 weeks | A successful response in overall BP control rate was defined as msSBP \< 140 mmHg and msDBP \<90 mmHg. |
| Percentage of Participants Achieving a Successful msSBP Response | 8 weeks | Successful msSBP response was defined as \< 140 mmHg or ≥ 20 mmHg reduction from baseline. |
| Percentage of Participants Achieving a Successful msDBP Response | 8 weeks | Successfull msDBP response was defined as \<90 mmHg or ≥10 mmHg reduction from baseline. |
| Change From Baseline in Mean 24-hour Ambulatory SBP (maSBP) at Week 8 | Baseline, 8 weeks | Ambulatory blood pressure monitoring (ABPM) over a 24-hour period was conducted at two time-points during the study in a subset of participants. |
| Change From Baseline in maSBP and maDBP for Daytime/Nighttime | Baseline, 8 weeks | ABPM over a 24-hour period was conducted at two time-points during the study in a subset of participants. |
| Change From Baseline in Office Pulse Pressure | Baseline, 8 weeks | Office pulse pressure was calculated as msSBP minus msDBP. Sitting blood pressure (BP) measurement was performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurement. The 4 measurements were summed and then averaged to calculate the mean BP value. The baseline PP value was subtracted from the week 8 PP value to determine the change from baseline in PP. |
| Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure | Baseline, 8 weeks | Ambulatory pulse pressure was calculated as hourly ambulatory SBP minus hourly ambulatory DBP in a subset of participants. |
| Number of Patients With Adverse Events, Serious Adverse Events and Death | 8 weeks | Participants were monitored for adverse events, serious adverse events and deaths throughout the study. |
| Change From Baseline in Mean 24-hour Ambulatory DBP (maDBP) at Week 8 | Baseline, 8 weeks | ABPM over a 24-hour period was conducted at two time-points during the study in a subset of participants. |
Countries
Japan
Participant flow
Recruitment details
The study consisted of 3 epochs: 1)screening, 2) single blind run-in and 3) double blind treatment. During the run-in epoch, eligible participants received placebo to both treatments for 2 to 4 weeks. After the run-in epoch, a total of 1161 eligible participants continued into the double blind treatment epoch for 8 weeks.
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 200 mg LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks | 387 |
| LCZ696 400 mg LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks | 385 |
| Olmesartan 20 mg Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks | 389 |
| Total | 1,161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 6 | 12 |
| Overall Study | Lack of Efficacy | 4 | 4 | 10 |
| Overall Study | Non-compliance with study treatment | 0 | 1 | 0 |
| Overall Study | Physician Decision | 3 | 2 | 2 |
| Overall Study | Technical Problems | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | LCZ696 400 mg | LCZ696 200 mg | Olmesartan 20 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 58.7 Years STANDARD_DEVIATION 10.5 | 57.9 Years STANDARD_DEVIATION 10.87 | 59.6 Years STANDARD_DEVIATION 10.5 | 58.7 Years STANDARD_DEVIATION 10.64 |
| Sex: Female, Male Female | 117 Participants | 123 Participants | 103 Participants | 343 Participants |
| Sex: Female, Male Male | 268 Participants | 264 Participants | 286 Participants | 818 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 | 48 / 387 | 47 / 385 | 46 / 389 |
| serious Total, serious adverse events | 1 / 387 | 1 / 385 | 7 / 389 |
Outcome results
Primary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurements. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline.
Time frame: Baseline, 8 weeks
Population: Full Analysis Set (FAS): The full analysis set included all randomized participants who received study medication and had both baseline and post-baseline BP assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | -18.21 mmHg | Standard Error 0.702 |
| LCZ696 400 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | -20.18 mmHg | Standard Error 0.704 |
| Olmesartan 20 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | -13.20 mmHg | Standard Error 0.7 |
Secondary
Change From Baseline in maSBP and maDBP for Daytime/Nighttime
ABPM over a 24-hour period was conducted at two time-points during the study in a subset of participants.
Time frame: Baseline, 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maSBP daytime | -12.60 mmHg | Standard Error 0.747 |
| LCZ696 200 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maSBP nighttime | -15.13 mmHg | Standard Error 0.747 |
| LCZ696 200 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maDBP daytime | -7.01 mmHg | Standard Error 0.506 |
| LCZ696 200 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maDBP nighttime | -8.82 mmHg | Standard Error 0.506 |
| LCZ696 400 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maDBP nighttime | -9.42 mmHg | Standard Error 0.506 |
| LCZ696 400 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maSBP nighttime | -16.09 mmHg | Standard Error 0.747 |
| LCZ696 400 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maSBP daytime | -14.44 mmHg | Standard Error 0.747 |
| LCZ696 400 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maDBP daytime | -8.00 mmHg | Standard Error 0.506 |
| Olmesartan 20 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maSBP daytime | -7.87 mmHg | Standard Error 0.776 |
| Olmesartan 20 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maSBP nighttime | -10.65 mmHg | Standard Error 0.776 |
| Olmesartan 20 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maDBP daytime | -4.95 mmHg | Standard Error 0.526 |
| Olmesartan 20 mg | Change From Baseline in maSBP and maDBP for Daytime/Nighttime | maDBP nighttime | -6.79 mmHg | Standard Error 0.526 |
Secondary
Change From Baseline in Mean 24-hour Ambulatory DBP (maDBP) at Week 8
ABPM over a 24-hour period was conducted at two time-points during the study in a subset of participants.
Time frame: Baseline, 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean 24-hour Ambulatory DBP (maDBP) at Week 8 | -7.65 mmHg | Standard Error 0.295 |
| LCZ696 400 mg | Change From Baseline in Mean 24-hour Ambulatory DBP (maDBP) at Week 8 | -8.44 mmHg | Standard Error 0.295 |
| Olmesartan 20 mg | Change From Baseline in Mean 24-hour Ambulatory DBP (maDBP) at Week 8 | -5.56 mmHg | Standard Error 0.307 |
Secondary
Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure
Ambulatory pulse pressure was calculated as hourly ambulatory SBP minus hourly ambulatory DBP in a subset of participants.
Time frame: Baseline, 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure | -5.79 mmHg | Standard Error 0.208 |
| LCZ696 400 mg | Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure | -6.57 mmHg | Standard Error 0.207 |
| Olmesartan 20 mg | Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure | -3.20 mmHg | Standard Error 0.216 |
Secondary
Change From Baseline in Mean 24-hour Ambulatory SBP (maSBP) at Week 8
Ambulatory blood pressure monitoring (ABPM) over a 24-hour period was conducted at two time-points during the study in a subset of participants.
Time frame: Baseline, 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean 24-hour Ambulatory SBP (maSBP) at Week 8 | -13.44 mmHg | Standard Error 0.445 |
| LCZ696 400 mg | Change From Baseline in Mean 24-hour Ambulatory SBP (maSBP) at Week 8 | -14.99 mmHg | Standard Error 0.445 |
| Olmesartan 20 mg | Change From Baseline in Mean 24-hour Ambulatory SBP (maSBP) at Week 8 | -8.78 mmHg | Standard Error 0.462 |
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
Sitting BP measurement was performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurement. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline.
Time frame: Baseline, 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | -7.76 mmHg | Standard Error 0.404 |
| LCZ696 400 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | -8.79 mmHg | Standard Error 0.406 |
| Olmesartan 20 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | -5.91 mmHg | Standard Error 0.404 |
Secondary
Change From Baseline in Office Pulse Pressure
Office pulse pressure was calculated as msSBP minus msDBP. Sitting blood pressure (BP) measurement was performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurement. The 4 measurements were summed and then averaged to calculate the mean BP value. The baseline PP value was subtracted from the week 8 PP value to determine the change from baseline in PP.
Time frame: Baseline, 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Office Pulse Pressure | -10.49 mmHg | Standard Error 0.471 |
| LCZ696 400 mg | Change From Baseline in Office Pulse Pressure | -11.30 mmHg | Standard Error 0.472 |
| Olmesartan 20 mg | Change From Baseline in Office Pulse Pressure | -7.34 mmHg | Standard Error 0.47 |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events and Death
Participants were monitored for adverse events, serious adverse events and deaths throughout the study.
Time frame: 8 weeks
Population: Safety Set. The safety set included aqll participants who had received study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 200 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Seroius Adverse Events | 1 Participants |
| LCZ696 200 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Adverse Events (serious and non-serious) | 135 Participants |
| LCZ696 200 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| LCZ696 400 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Seroius Adverse Events | 1 Participants |
| LCZ696 400 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Adverse Events (serious and non-serious) | 136 Participants |
| LCZ696 400 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Olmesartan 20 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Adverse Events (serious and non-serious) | 152 Participants |
| Olmesartan 20 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Olmesartan 20 mg | Number of Patients With Adverse Events, Serious Adverse Events and Death | Seroius Adverse Events | 7 Participants |
Secondary
Percentage of Participants Achieving a Successful msDBP Response
Successfull msDBP response was defined as \<90 mmHg or ≥10 mmHg reduction from baseline.
Time frame: 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Percentage of Participants Achieving a Successful msDBP Response | 69.5 Percentage of participants |
| LCZ696 400 mg | Percentage of Participants Achieving a Successful msDBP Response | 70.1 Percentage of participants |
| Olmesartan 20 mg | Percentage of Participants Achieving a Successful msDBP Response | 60.7 Percentage of participants |
Secondary
Percentage of Participants Achieving a Successful msSBP Response
Successful msSBP response was defined as \< 140 mmHg or ≥ 20 mmHg reduction from baseline.
Time frame: 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Percentage of Participants Achieving a Successful msSBP Response | 57.9 Percentage of participants |
| LCZ696 400 mg | Percentage of Participants Achieving a Successful msSBP Response | 63.1 Percentage of participants |
| Olmesartan 20 mg | Percentage of Participants Achieving a Successful msSBP Response | 42.9 Percentage of participants |
Secondary
Percentage of Participants Achieving a Successful Response in Overall Blood Pressure Control at Week 8
A successful response in overall BP control rate was defined as msSBP \< 140 mmHg and msDBP \<90 mmHg.
Time frame: 8 weeks
Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Percentage of Participants Achieving a Successful Response in Overall Blood Pressure Control at Week 8 | 43.9 Percentage of participants |
| LCZ696 400 mg | Percentage of Participants Achieving a Successful Response in Overall Blood Pressure Control at Week 8 | 46.5 Percentage of participants |
| Olmesartan 20 mg | Percentage of Participants Achieving a Successful Response in Overall Blood Pressure Control at Week 8 | 32.9 Percentage of participants |