Hypertension
Conditions
Keywords
LCZ696,, Hypertension,, Aortic stiffness,, Central blood pressure,, Cardiovascular MRI
Brief summary
This was the first evaluation of the effects of LCZ696 on local and regional measures of aortic stiffness in subjects with mild to moderate hypertension and widened pulse pressure. The results of this exploratory study will help to understand the mechanism of action of LCZ696 and used to inform the design of future clinical studies with LCZ696 in subjects with cardiovascular diseases.
Interventions
200 mg tablets
DRUGolmesartan
OTHERplacebo to sacubitril/valsartan (LCZ696)
placebo
OTHERplacebo to olmesartan
placebo
DRUGAmlodipine (Optional)
If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen
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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subjects with essential hypertension, untreated or currently taking antihypertensive therapy Key
Exclusion criteria
* women of child bearing potential (WOCBP) if not on highly effective contraception * Malignant or severe hypertension (grade 3 of WHO classification) * History or evidence of a secondary form of hypertension * Transient ischemic cerebral attack (TIA) during the 12 months prior to screening or any history of stroke. * Previous or current diagnosis of heart failure (New York Heart Association Class II-IV).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Ascending Aorta Distensibility at 52 Week | Baseline, 52 weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Ascending aorta distensibility was one of the 3 components for measuring local arota distensibility. |
| Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks | Baseline, 52 weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Proximal descending aorta distensibility was one of the 3 components for measuring local arota distensibility. |
| Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks | Baseline, 52 weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Distal descending aorta distensibility was one of the 3 components for measuring local arota distensibility. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Augmentation Pressure at 52 Weeks | Baseline, 52 weeks | Augmentation pressure is the added pressure during systole due to wave reflection. |
| Change From Baseline in Augmentation Index at 52 Weeks | Baseline, 52 weeks | Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection. |
| Change From Baseline in Local Aortic Strain at 52 Weeks | Baseline, 52 weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic strain. Local aortic strain was measured by assessing ascending aorta strain, proximal descending aorta strain and distal descending aorta strain. |
| Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | 12 weeks | This outcome measure summarizes patients with any adverse events, serious adverse events and death. |
| Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks | Baseline, 52 weeks | For pulse wave velocity calculation, the pressure waveform at the femoral site (using a partially inflated custom blood pressure cuff) and the carotid site (using hand -held applanation tonometry) were measured simultaneously. Pulse wave analysis was performed on the central aortic pressure waveform as derived from the brachial pressure waveform recorded in a partially-inflated blood pressure cuff around the upper arm. |
| Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks | Baseline, 52 weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of regional aortic pulse wave velocity. |
| Change From Baseline in Central Blood Pressure at 52 Weeks | Baseline, 52 weeks | Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure. |
Countries
Germany, Switzerland, United Kingdom
Participant flow
Recruitment details
A total of 115 patients were enrolled. One patient was discontinued after randomization before receiving any dose of study randomized medication. A total of 114 patients received study randomized medication
Participants by arm
| Arm | Count |
|---|---|
| Sacubitril/Valsartan (LCZ696) LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target) | 57 |
| Olmesartan Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target) | 57 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Add-on Period (40 Weeks) | Adverse Event | 0 | 1 |
| Add-on Period (40 Weeks) | Patient withdrew consent | 1 | 0 |
| Add-on Period (40 Weeks) | Protocol deviation | 1 | 1 |
| Add-on Period (40 Weeks) | Unsatisfactory therapeutic effect | 1 | 0 |
| Single Drug Treatment (12 Weeks) | Administrative problems | 3 | 2 |
| Single Drug Treatment (12 Weeks) | Adverse Event | 0 | 1 |
| Single Drug Treatment (12 Weeks) | Protocol deviation | 0 | 1 |
Baseline characteristics
| Characteristic | Sacubitril/Valsartan (LCZ696) | Olmesartan | Total |
|---|---|---|---|
| Age, Continuous | 60.5 Years STANDARD_DEVIATION 7.8 | 59.2 Years STANDARD_DEVIATION 13.1 | 59.8 Years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 37 Participants |
| Sex: Female, Male Male | 37 Participants | 40 Participants | 77 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 57 | 6 / 57 | 10 / 57 | 14 / 56 | 16 / 54 | 24 / 53 |
| serious Total, serious adverse events | 0 / 57 | 2 / 57 | 0 / 57 | 2 / 56 | 6 / 54 | 5 / 53 |
Outcome results
Primary
Change From Baseline in Ascending Aorta Distensibility at 52 Week
Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Ascending aorta distensibility was one of the 3 components for measuring local arota distensibility.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Ascending Aorta Distensibility at 52 Week | 0.269 10^(-3) x mmHg^(-1) | Standard Error 0.1283 |
| Olmesartan | Change From Baseline in Ascending Aorta Distensibility at 52 Week | 0.330 10^(-3) x mmHg^(-1) | Standard Error 0.1233 |
p-value: 0.732495% CI: [-0.4178, 0.2947]Linear Model
Primary
Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks
Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Distal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks | 0.417 10^(-3) x mmHg^(-1) | Standard Error 0.2242 |
| Olmesartan | Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks | 0.498 10^(-3) x mmHg^(-1) | Standard Error 0.2156 |
p-value: 0.794695% CI: [-0.6987, 0.5362]Linear Model
Primary
Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks
Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Proximal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks | 0.510 10^(-3) x mmHg^(-1) | Standard Error 0.1528 |
| Olmesartan | Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks | 0.547 10^(-3) x mmHg^(-1) | Standard Error 0.1469 |
p-value: 0.861495% CI: [-0.4582, 0.3839]Linear Model
Secondary
Change From Baseline in Augmentation Index at 52 Weeks
Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Augmentation Index at 52 Weeks | -2.385 percent | Standard Error 1.1805 |
| Olmesartan | Change From Baseline in Augmentation Index at 52 Weeks | -1.515 percent | Standard Error 1.1805 |
Secondary
Change From Baseline in Augmentation Pressure at 52 Weeks
Augmentation pressure is the added pressure during systole due to wave reflection.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Augmentation Pressure at 52 Weeks | -2.443 mmHg | Standard Error 0.595 |
| Olmesartan | Change From Baseline in Augmentation Pressure at 52 Weeks | -1.437 mmHg | Standard Error 0.595 |
Secondary
Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks
For pulse wave velocity calculation, the pressure waveform at the femoral site (using a partially inflated custom blood pressure cuff) and the carotid site (using hand -held applanation tonometry) were measured simultaneously. Pulse wave analysis was performed on the central aortic pressure waveform as derived from the brachial pressure waveform recorded in a partially-inflated blood pressure cuff around the upper arm.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks | -0.428 meters per second (m/s) | Standard Error 0.1663 |
| Olmesartan | Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks | -0.434 meters per second (m/s) | Standard Error 0.1663 |
Secondary
Change From Baseline in Central Blood Pressure at 52 Weeks
Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Central Blood Pressure at 52 Weeks | Central systolic blood pressure | -16.655 mmHg | Standard Error 1.4968 |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Central Blood Pressure at 52 Weeks | Central diastolic blood pressure | -10.318 mmHg | Standard Error 1.0578 |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Central Blood Pressure at 52 Weeks | Central pulse pressure | -6.539 mmHg | Standard Error 0.9428 |
| Olmesartan | Change From Baseline in Central Blood Pressure at 52 Weeks | Central systolic blood pressure | -13.625 mmHg | Standard Error 1.4968 |
| Olmesartan | Change From Baseline in Central Blood Pressure at 52 Weeks | Central diastolic blood pressure | -10.432 mmHg | Standard Error 1.0578 |
| Olmesartan | Change From Baseline in Central Blood Pressure at 52 Weeks | Central pulse pressure | -3.041 mmHg | Standard Error 0.9428 |
Secondary
Change From Baseline in Local Aortic Strain at 52 Weeks
Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic strain. Local aortic strain was measured by assessing ascending aorta strain, proximal descending aorta strain and distal descending aorta strain.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Local Aortic Strain at 52 Weeks | Ascending Aorta Strain | -0.830 percent | Standard Error 0.7903 |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Local Aortic Strain at 52 Weeks | Proximal Descending Aorta Strain | -0.284 percent | Standard Error 0.894 |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Local Aortic Strain at 52 Weeks | Distal Descending Aorta Strain | -1.092 percent | Standard Error 1.0956 |
| Olmesartan | Change From Baseline in Local Aortic Strain at 52 Weeks | Ascending Aorta Strain | 0.453 percent | Standard Error 0.7598 |
| Olmesartan | Change From Baseline in Local Aortic Strain at 52 Weeks | Proximal Descending Aorta Strain | -0.066 percent | Standard Error 0.8596 |
| Olmesartan | Change From Baseline in Local Aortic Strain at 52 Weeks | Distal Descending Aorta Strain | 0.225 percent | Standard Error 1.0533 |
Secondary
Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks
Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of regional aortic pulse wave velocity.
Time frame: Baseline, 52 weeks
Population: Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks | -2.086 meters per second (m/s) | Standard Error 0.5029 |
| Olmesartan | Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks | -1.085 meters per second (m/s) | Standard Error 0.4835 |
Secondary
Number of Patients With Reported Adverse Events, Serious Adverse Events and Death
This outcome measure summarizes patients with any adverse events, serious adverse events and death.
Time frame: 12 weeks
Population: Safety analysis set: All patients that received study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 0 Patients |
| Sacubitril/Valsartan (LCZ696) | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Any Adverse events | 13 Patients |
| Sacubitril/Valsartan (LCZ696) | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Olmesartan | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 2 Patients |
| Olmesartan | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Any Adverse events | 16 Patients |
| Olmesartan | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg) | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 0 Patients |
| Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg) | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Any Adverse events | 21 Patients |
| Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg) | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Maintenance Dose: Olmesartan 40 mg | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 2 Patients |
| Maintenance Dose: Olmesartan 40 mg | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Any Adverse events | 28 Patients |
| Maintenance Dose: Olmesartan 40 mg | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 6 Patients |
| Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Any Adverse events | 31 Patients |
| Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Olmesartan 40mg +/- Amlodipine | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Any Adverse events | 38 Patients |
| Olmesartan 40mg +/- Amlodipine | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Olmesartan 40mg +/- Amlodipine | Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 5 Patients |