Hypertension
Conditions
Keywords
hypertension,, LCZ696,, olmesartan
Brief summary
This study will assess the efficacy and safety of LCZ696 in comparison to olmesartan in essential hypertensive patients not adequately responsive to olmesartan
Interventions
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 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 drugs within 4 weeks prior to first visit) must have an office msSBP ≥ 145 mmHg and \< 180 mmHg after washout epoch and after 4 weeks run-in epoch * untreated patients (either newly diagnosed or those patients with a history of hypertension but have not been taking any antihypertensive drugs for at least 4 weeks prior to first visit) must have an offcie msSBP ≥ 150 mmHg and \< 180 mmHg at screening and 1 week after screening and must have an office msSBP ≥ 145 mmHg and \< 180 mmHg after 4 weeks run-in epoch * patients must successfully complete ABPM and pass technical requirements to be qualified for randomization
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, 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 (PKD), drug-induced hypertension * Patients who previously entered a LCZ696 study and had been randomized or enrolled to receive active drug treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-hour Mean Ambulatory Systolic Blood Pressure (maSBP) | baseline, 8 weeks | Twenty-four hour mean ambulatory blood pressure measurements (ABPM) will be performed at baseline and at end of study (week 8). The first 24-hour ABPM will be performed beginning at 24 hours prior to baseline visit and the second will be performed 24 hours prior to week 8 visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | baseline, 8 weeks | Sitting blood pressure (BP) measurement will be taken at every visit from screening through end of study. For each participant at each visit, four separate sitting BP measurements will be obtained (with a full two minute interval between measurements) and averaged to obtain the mean |
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | baseline, 8 weeks | Sitting blood pressure (BP) measurement will be taken at every visit from screening through end of study. For each participant at each visit, four separate sitting BP measurements will be obtained (with a full two minute interval between measurements) and averaged to obtain the mean |
| Change From Baseline in Office Pulse Pressure | baseline, 8 weeks | Mean sitting pulse pressure (msPP) will be calculated at screening through end of study at every visit. Mean sitting pulse pressure is calculated as msSBP-msDBP. |
| Number of Patients Achieving Successful Overall Blood Pressure Control | 8 weeks | Successful overall blood pressure control is defined as both msSBP/msDBP \<140/90 mmHg |
| Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (maDBP) | baseline, 8 weeks | Twenty-four hour mean ambulatory blood pressure measurements (ABPM) will be performed at baseline and at end of study (week 8). The 24-hour ABPM measurements are performed beginning 24 hours prior to baseline and week 8 visits. |
| Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Control | 8 weeks | Successful mean sitting diastolic blood pressure control is defined as msDBP \<90 mmHg |
| Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Response | baseline, 8 weeks | Successful mean sitting systolic blood pressure response is defined as msSBP \<140 mmHg or a reduction ≥ 20 mmHg from baseline. |
| Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Response | baseline, 8 weeks | Successful mean sitting diastolic blood pressure response is defined as msDBP \<90 mmHg or a reduction ≥10 mmHg from baseline. |
| Number of Patients With Total Adverse Events, Serious Adverse Events and Death | 8 weeks | Number of patients with total adverse events, serious adverse events and death were reported. |
| Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Control | 8 weeks | Successful mean sitting systolic blood pressure control is defined as msSBP \<140 mmHg |
Countries
Argentina, Guatemala, Philippines, Puerto Rico, Russia, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 200 mg Patients will be treated with one LCZ696 200 mg tablet and one placebo of olmesartan 20 mg capsule once daily for 8 weeks. | 188 |
| Olmesartan 20 mg Patients will be treated with one placebo of LCZ696 200 mg tablet and one olmesartan 20 mg capsule once daily for 8 weeks. | 187 |
| Total | 375 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance with study treatment | 0 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Protocol deviation | 3 | 3 |
| Overall Study | Subject/guardian decision | 3 | 1 |
Baseline characteristics
| Characteristic | LCZ696 200 mg | Olmesartan 20 mg | Total |
|---|---|---|---|
| Age, Continuous | 57.1 Years STANDARD_DEVIATION 10.19 | 58.0 Years STANDARD_DEVIATION 9.09 | 57.6 Years STANDARD_DEVIATION 9.65 |
| Sex: Female, Male Female | 91 Participants | 92 Participants | 183 Participants |
| Sex: Female, Male Male | 97 Participants | 95 Participants | 192 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 188 | 10 / 187 |
| serious Total, serious adverse events | 0 / 188 | 2 / 187 |
Outcome results
Primary
Change From Baseline in 24-hour Mean Ambulatory Systolic Blood Pressure (maSBP)
Twenty-four hour mean ambulatory blood pressure measurements (ABPM) will be performed at baseline and at end of study (week 8). The first 24-hour ABPM will be performed beginning at 24 hours prior to baseline visit and the second will be performed 24 hours prior to week 8 visit.
Time frame: baseline, 8 weeks
Population: A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in 24-hour Mean Ambulatory Systolic Blood Pressure (maSBP) | -4.26 mmHg | Standard Error 0.6 |
| Olmesartan 20 mg | Change From Baseline in 24-hour Mean Ambulatory Systolic Blood Pressure (maSBP) | -1.04 mmHg | Standard Error 0.61 |
p-value: <0.00195% CI: [-4.73, -1.65]ANCOVA
Secondary
Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (maDBP)
Twenty-four hour mean ambulatory blood pressure measurements (ABPM) will be performed at baseline and at end of study (week 8). The 24-hour ABPM measurements are performed beginning 24 hours prior to baseline and week 8 visits.
Time frame: baseline, 8 weeks
Population: A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (maDBP) | -2.27 mmHg | Standard Error 0.39 |
| Olmesartan 20 mg | Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (maDBP) | -0.35 mmHg | Standard Error 0.39 |
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
Sitting blood pressure (BP) measurement will be taken at every visit from screening through end of study. For each participant at each visit, four separate sitting BP measurements will be obtained (with a full two minute interval between measurements) and averaged to obtain the mean
Time frame: baseline, 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | -7.52 mmHg | Standard Error 0.7 |
| Olmesartan 20 mg | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | -4.47 mmHg | Standard Error 0.71 |
Secondary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Sitting blood pressure (BP) measurement will be taken at every visit from screening through end of study. For each participant at each visit, four separate sitting BP measurements will be obtained (with a full two minute interval between measurements) and averaged to obtain the mean
Time frame: baseline, 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | -14.21 mmHg | Standard Error 1.28 |
| Olmesartan 20 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | -10.03 mmHg | Standard Error 1.29 |
Secondary
Change From Baseline in Office Pulse Pressure
Mean sitting pulse pressure (msPP) will be calculated at screening through end of study at every visit. Mean sitting pulse pressure is calculated as msSBP-msDBP.
Time frame: baseline, 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Office Pulse Pressure | -6.67 mmHg | Standard Error 0.94 |
| Olmesartan 20 mg | Change From Baseline in Office Pulse Pressure | -5.54 mmHg | Standard Error 0.94 |
Secondary
Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Control
Successful mean sitting diastolic blood pressure control is defined as msDBP \<90 mmHg
Time frame: 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Control | 133 Participants |
| Olmesartan 20 mg | Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Control | 112 Participants |
Secondary
Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Response
Successful mean sitting diastolic blood pressure response is defined as msDBP \<90 mmHg or a reduction ≥10 mmHg from baseline.
Time frame: baseline, 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Response | 137 Participants |
| Olmesartan 20 mg | Number of Patients Achieving Successful Mean Sitting Diastolic Blood Pressure (msDBP) Response | 115 Participants |
Secondary
Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Control
Successful mean sitting systolic blood pressure control is defined as msSBP \<140 mmHg
Time frame: 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Control | 84 Participants |
| Olmesartan 20 mg | Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Control | 58 Participants |
Secondary
Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Response
Successful mean sitting systolic blood pressure response is defined as msSBP \<140 mmHg or a reduction ≥ 20 mmHg from baseline.
Time frame: baseline, 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Response | 90 Participants |
| Olmesartan 20 mg | Number of Patients Achieving Successful Mean Sitting Systolic Blood Pressure (msSBP) Response | 65 Participants |
Secondary
Number of Patients Achieving Successful Overall Blood Pressure Control
Successful overall blood pressure control is defined as both msSBP/msDBP \<140/90 mmHg
Time frame: 8 weeks
Population: Full Analysis Set (FAS) - All patients who were randomized. Following the intent to treat principle, patients were analyzed according to the treatment they were assigned to at the randomization. However, patients who were not qualified for randomization and were inadvertently randomized into the study were excluded from the FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Number of Patients Achieving Successful Overall Blood Pressure Control | 76 Participants |
| Olmesartan 20 mg | Number of Patients Achieving Successful Overall Blood Pressure Control | 52 Participants |
Secondary
Number of Patients With Total Adverse Events, Serious Adverse Events and Death
Number of patients with total adverse events, serious adverse events and death were reported.
Time frame: 8 weeks
Population: Safety Set (SAF) - All patients who received at least one dose of study medication in the double-blind epoch. Patients were analyzed according to the treatment they received. One patient was not included in the SAF due to mis-randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 200 mg | Number of Patients With Total Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 44 Number of participants |
| LCZ696 200 mg | Number of Patients With Total Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 0 Number of participants |
| LCZ696 200 mg | Number of Patients With Total Adverse Events, Serious Adverse Events and Death | Deaths | 0 Number of participants |
| Olmesartan 20 mg | Number of Patients With Total Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 41 Number of participants |
| Olmesartan 20 mg | Number of Patients With Total Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 2 Number of participants |
| Olmesartan 20 mg | Number of Patients With Total Adverse Events, Serious Adverse Events and Death | Deaths | 0 Number of participants |