Heart Failure, Reduced Ejection Fraction
Conditions
Keywords
Heart failure with reduced left ventricular ejection fraction (LVEF), Cardiac dysfunction, Heart muscle dysfunction, Left ventricular (LV) dilation, Left ventricular hypertrophy, HF, AHF, CHF, acute heart failure, chronic heart failure, congestive heart failure, congestive cardiac failure, Heart failure, HReEF, Physical Activity, Actigraphy, Home sleep test, wake
Brief summary
The purpose of this study was to investigate the effects of initiation of sacubitril/valsartan vs enalapril treatment on objective measures of both waking activity and sleep in subjects with heart failure with reduced ejection fraction.
Interventions
sacubitril/valsartan tablet taken orally.
DRUGenalapril
Enalapril tablet taken orally.
DRUGmatching placebo sacubitril/valsartan (LCZ696)
matching placebo sacubitril/valsartan tablet taken orally
DRUGmatching placebo enalapril
matching placebo enalapril tablet taken orally
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Written informed consent must be obtained before any assessment is performed. * Men and women between 18 and 80 years of age * Subjects diagnosed with NYHA class II or III heart failure and with reduced ejection (HFrEF). (Reduced ejection is defined as left ventricular EF ≤ 40%. LVEF ≤40% may be determined via any local measurement within the past 6 months prior to signing consent, using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography provided no subsequent study documenting an EF of \>40%. If the EF measurement is expressed as a value range, the average of the range endpoint values should be used as the EF). * Subjects must be a candidate for treatment with sacubitril/valsartan as per USPI. * Subjects must be living in a traditional residence, apartment, or non-communal adult home where they can move about freely and frequently and are primarily responsible for scheduling their sleep and daily activities. Key
Exclusion criteria
* Subjects with a history of hypersensitivity to any of the study drugs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs. * Subjects with a history of angioedema drug related or otherwise * Subjects with symptomatic hypotension or systolic blood pressure \<100 mmHg at screening or \<95 mmHg at randomization * Subjects with any conditions in skin or upper extremities which would limit the ability to tolerate a wrist-worn actigraphy device on the non-dominant arm for 24 hours/day for the duration of the study. * Subjects who are non-ambulatory or use mobility assistive devices such as motorized devices, wheelchairs, or walkers. The use of canes for stability while ambulating is acceptable. * Subjects with physical activity impairment primarily due to conditions other than heart failure such as: * Exertional angina inflammatory or degenerative joint disease -gout * peripheral vascular disease * neurologic disease affecting activity or mobility
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline | Baseline, week 8 | The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio \> 1 indicates an increase in mean activity counts from baseline to week 8. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1 | Baseline, Week 1 | Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). |
| Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 | Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16 | Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). |
| Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8 | Baseline, Week 8 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). |
| Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1 | Baseline, Week 1 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). |
| Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 | Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). |
Countries
United States
Participant flow
Recruitment details
140 subjects from 23 sites in the US were randomized. The study consisted of a 2-week baseline period , followed by an 8-week double-blind treatment period ( randomized to sacubitril/valsartan or enalapril, in a 1:1 ratio), followed by an 8-week open label extension period during which all patients were treated with sacubitril/valsartan.
Participants by arm
| Arm | Count |
|---|---|
| Enalapril Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan | 70 |
| Sacubitril/Valsartan Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan | 70 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Period | Adverse Event | 4 | 0 |
| Double-blind Period | Death | 1 | 0 |
| Double-blind Period | Physician Decision | 0 | 2 |
| Double-blind Period | Study terminated by sponsor | 1 | 2 |
| Double-blind Period | Withdrawal by Subject | 2 | 2 |
| Open-label Period | Adverse Event | 1 | 0 |
| Open-label Period | Physician Decision | 1 | 0 |
| Open-label Period | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Enalapril | Sacubitril/Valsartan | Total |
|---|---|---|---|
| Age, Continuous | 64.2 years | 62.3 years | 63.3 years |
| Race/Ethnicity, Customized Asian | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Black | 8 Participants | 13 Participants | 21 Participants |
| Race/Ethnicity, Customized Caucasian | 60 Participants | 48 Participants | 108 Participants |
| Race/Ethnicity, Customized Native American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 14 Participants | 18 Participants | 32 Participants |
| Sex: Female, Male Male | 56 Participants | 52 Participants | 108 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 70 | 0 / 69 | 0 / 62 | 0 / 64 |
| other Total, other adverse events | 26 / 70 | 8 / 69 | 11 / 62 | 11 / 64 |
| serious Total, serious adverse events | 4 / 70 | 5 / 69 | 4 / 62 | 3 / 64 |
Outcome results
Primary
Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline
The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio \> 1 indicates an increase in mean activity counts from baseline to week 8.
Time frame: Baseline, week 8
Population: Full Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril | Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline | 1.0411 Ratio |
| Sacubitril/Valsartan | Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline | 0.9844 Ratio |
p-value: 0.089595% CI: [0.8863, 1.0088]ANCOVA
Secondary
Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1
Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).
Time frame: Baseline, Week 1
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1 | 171.3 counts | Standard Error 440.9 |
| Sacubitril/Valsartan | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1 | 464.9 counts | Standard Error 421.8 |
p-value: 0.631695% CI: [-916.5, 1503.8]ANCOVA
Secondary
Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16
Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).
Time frame: Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enalapril | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 | Week 9 (change from Baseline) | -198.8 counts | Standard Deviation 5245.5 |
| Enalapril | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 | Week 16 (change from Baseline) | -455.1 counts | Standard Deviation 4966.7 |
| Sacubitril/Valsartan | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 | Week 9 (change from Baseline) | -402.9 counts | Standard Deviation 5857 |
| Sacubitril/Valsartan | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 | Week 16 (change from Baseline) | 46.9 counts | Standard Deviation 4811.2 |
Secondary
Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1
Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).
Time frame: Baseline, Week 1
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1 | 0.169 counts/minute | Standard Error 0.696 |
| Sacubitril/Valsartan | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1 | 2.647 counts/minute | Standard Error 0.674 |
p-value: 0.012195% CI: [0.553, 4.403]ANCOVA
Secondary
Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8
Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).
Time frame: Baseline, Week 8
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8 | 0.339 counts/minute | Standard Error 0.752 |
| Sacubitril/Valsartan | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8 | 2.377 counts/minute | Standard Error 0.746 |
p-value: 0.05795% CI: [-0.062, 4.138]ANCOVA
Secondary
Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16
Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).
Time frame: Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enalapril | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 | Week 16 (change from Baseline) | 1.066 counts/minute | Standard Deviation 5.367 |
| Enalapril | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 | Week 9 (change from Baseline) | 2.158 counts/minute | Standard Deviation 5.15 |
| Sacubitril/Valsartan | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 | Week 9 (change from Baseline) | 3.230 counts/minute | Standard Deviation 7.269 |
| Sacubitril/Valsartan | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 | Week 16 (change from Baseline) | 1.489 counts/minute | Standard Deviation 5.642 |