Essential Hypertension
Conditions
Keywords
hypertension, blood pressure, LCZ696, dual-acting, neprilysin, nep inhibitor, vasopeptidase, angiotensin receptor, angiotensin receptor neprilysin inhibitor (ARNi)
Brief summary
The purpose of this study is to assess the long-term safety, tolerability and efficacy of LCZ696.
Interventions
DRUGLCZ696
Participants received LCZ696 200 mg as the starting dose with optional down titration to 100 mg for tolerance and optional up titration to 400 mg for adequate blood pressure control.
DRUGAmlodipine
Optional add-on of amlodipine (5-10 mg) was allowed (as applicable per local country regulations) for adequate blood pressure control.
Optional add-on of hydrochlorothiazide (HCTZ) (12.5-25 mg) was allowed (as applicable per local country regulations) for adequate blood pressure control.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patients who have successfully completed protocol No. CLCZ696A2219 and who, as judged by the study investigator, are able to continue in the current study. * Ability to communicate and comply with all study requirements and demonstrate good medication compliance during CLCZ696A2219.
Exclusion criteria
* Patients who did not complete CLCZ696A2219. * Presence of significant protocol violation in CLCZ696A2219. * Patients who are deemed to be unable to comply with the protocol by the investigator. * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Baseline to 12 months | Participants were monitored throughout the study for adverse events, serious adverse events and deaths. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | Baseline, 12 months | Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement. |
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy) | Baseline, 12 months | Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement. |
| Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment) | Baseline to 12 months | Blood pressure (BP) control is defined as BP \<140/90 mmHg. |
| Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Mono or Combination Therapy) | Baseline to 12 months | Blood pressure (BP) control is defined as BP \<140/90 mmHg. |
Countries
China, Japan, South Korea, Taiwan, Thailand
Participant flow
Recruitment details
Analyses on this open label extension study were performed according to treatment groups defined by the maximum and highest dose treatments received: 1) LCZ696 200 mg, 2) LCZ696 400 mg, 3) LCZ696 400 mg/Amlodipine, 4) LCZ696 400 mg/Amlodipine/HCTZ, 5) LCZ696 Mono (LCZ696 only), and 6) LCZ696 Combination LCZ696 with Amlodipine and/or HCTZ).
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 200 mg Participants received LCZ696 200 mg by mouth once daily (qd). | 139 |
| LCZ696 400 mg Participants received LCZ696 400 mg by mouth qd. | 89 |
| LCZ606 400 mg/Amlodipine Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn). | 109 |
| LCZ696 400 mg/Amlodipine/HCTZ Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn. | 4 |
| Total | 341 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Extension by Maximum Treatment | Adverse Event | 4 | 2 | 1 | 0 | 0 | 0 |
| Extension by Maximum Treatment | Lack of Efficacy | 1 | 0 | 1 | 0 | 0 | 0 |
| Extension by Maximum Treatment | Lost to Follow-up | 1 | 2 | 0 | 0 | 0 | 0 |
| Extension by Maximum Treatment | Protocol deviation | 0 | 0 | 1 | 0 | 0 | 0 |
| Extension by Maximum Treatment | Withdrawal by Subject | 1 | 6 | 1 | 0 | 0 | 0 |
| Extension by Mono or Combination Therapy | Adverse Event | 0 | 0 | 0 | 0 | 6 | 1 |
| Extension by Mono or Combination Therapy | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 1 |
| Extension by Mono or Combination Therapy | Lost to Follow-up | 0 | 0 | 0 | 0 | 3 | 0 |
| Extension by Mono or Combination Therapy | Protocol deviation | 0 | 0 | 0 | 0 | 0 | 1 |
| Extension by Mono or Combination Therapy | Withdrawal by Subject | 0 | 0 | 0 | 0 | 7 | 1 |
Baseline characteristics
| Characteristic | LCZ696 200 mg | LCZ696 400 mg | LCZ606 400 mg/Amlodipine | LCZ696 400 mg/Amlodipine/HCTZ | Total |
|---|---|---|---|---|---|
| Age, Continuous | 52.2 Years STANDARD_DEVIATION 9.69 | 50.3 Years STANDARD_DEVIATION 10.14 | 52.5 Years STANDARD_DEVIATION 9.53 | 46.3 Years STANDARD_DEVIATION 2.06 | 51.8 Years STANDARD_DEVIATION 9.73 |
| Sex: Female, Male Female | 55 Participants | 18 Participants | 26 Participants | 0 Participants | 99 Participants |
| Sex: Female, Male Male | 84 Participants | 71 Participants | 83 Participants | 4 Participants | 242 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 12 | 77 / 340 | 39 / 201 | 32 / 112 | 0 / 4 |
| serious Total, serious adverse events | 1 / 12 | 10 / 340 | 2 / 201 | 0 / 112 | 0 / 4 |
Outcome results
Primary
Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment)
Participants were monitored throughout the study for adverse events, serious adverse events and deaths.
Time frame: Baseline to 12 months
Population: Actual extension treatment received: The participants are included in each treatment group for which they received treatment. For example, if a participant started on LCZ696 200 mg but was then down-titrated to LCZ696 100 mg, the participant was counted once in the LCZ696 100 mg group and once in the LCZ696 200 mg group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 200 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Adverse events (serious and non-serious) | 147 Participants |
| LCZ696 200 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Deaths | 0 Participants |
| LCZ696 200 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Seroius adverse events | 10 Participants |
| LCZ696 400 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Seroius adverse events | 2 Participants |
| LCZ696 400 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Adverse events (serious and non-serious) | 78 Participants |
| LCZ696 400 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Deaths | 0 Participants |
| LCZ606 400 mg/Amlodipine | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Seroius adverse events | 0 Participants |
| LCZ606 400 mg/Amlodipine | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Adverse events (serious and non-serious) | 53 Participants |
| LCZ606 400 mg/Amlodipine | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Deaths | 0 Participants |
| LCZ696 400 mg/Amlodipine/HCTZ | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Adverse events (serious and non-serious) | 0 Participants |
| LCZ696 400 mg/Amlodipine/HCTZ | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Deaths | 0 Participants |
| LCZ696 400 mg/Amlodipine/HCTZ | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Seroius adverse events | 0 Participants |
| LCZ696 100 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Seroius adverse events | 1 Participants |
| LCZ696 100 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Adverse events (serious and non-serious) | 6 Participants |
| LCZ696 100 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) | Deaths | 0 Participants |
Secondary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment)
Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.
Time frame: Baseline, 12 months
Population: Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 400 mg/Amlodopine group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msDBP | -16.6 mmHg | Standard Deviation 7.63 |
| LCZ696 200 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msSBP | -24.1 mmHg | Standard Deviation 12.16 |
| LCZ696 400 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msSBP | -21.3 mmHg | Standard Deviation 11.46 |
| LCZ696 400 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msDBP | -14.2 mmHg | Standard Deviation 7.05 |
| LCZ606 400 mg/Amlodipine | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msDBP | -17.4 mmHg | Standard Deviation 7.71 |
| LCZ606 400 mg/Amlodipine | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msSBP | -28.1 mmHg | Standard Deviation 13.43 |
| LCZ696 400 mg/Amlodipine/HCTZ | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msDBP | -16.8 mmHg | Standard Deviation 3.84 |
| LCZ696 400 mg/Amlodipine/HCTZ | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) | msSBP | -29.0 mmHg | Standard Deviation 9.23 |
Secondary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy)
Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.
Time frame: Baseline, 12 months
Population: Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 combination group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 200 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy) | msSBP | -23.0 mmHg | Standard Deviation 11.95 |
| LCZ696 200 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy) | msDBP | -15.7 mmHg | Standard Deviation 7.49 |
| LCZ696 400 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy) | msSBP | -28.2 mmHg | Standard Deviation 13.27 |
| LCZ696 400 mg | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy) | msDBP | -17.3 mmHg | Standard Deviation 7.6 |
Secondary
Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment)
Blood pressure (BP) control is defined as BP \<140/90 mmHg.
Time frame: Baseline to 12 months
Population: Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 400 mg/Amlodopine group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment) | 114 Participants |
| LCZ696 400 mg | Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment) | 62 Participants |
| LCZ606 400 mg/Amlodipine | Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment) | 77 Participants |
| LCZ696 400 mg/Amlodipine/HCTZ | Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment) | 3 Participants |
Secondary
Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Mono or Combination Therapy)
Blood pressure (BP) control is defined as BP \<140/90 mmHg.
Time frame: Baseline to 12 months
Population: Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 combination group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 200 mg | Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Mono or Combination Therapy) | 176 Participants |
| LCZ696 400 mg | Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Mono or Combination Therapy) | 80 Participants |