Study on the Effects of Sacubitril/Valsartan on Physical Activity and Sleep in Heart Failure With Reduced Ejection Fraction Patients.

Study Overview
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Brief Summary
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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.

Official Title
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Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study and 8-week Open Label Extension to Evaluate the Effect of Initiation of Sacubitril/Valsartan on Objective Measures of Waking Activity and Sleep, as Health-related Quality of Life Functions in Subjects With Heart Failure and Reduced Ejection Fraction (AWAKE-HF).

Conditions
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Heart Failure, Reduced Ejection Fraction

Intervention / Treatment
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* Drug: sacubitril/valsartan (LCZ696)
* Drug: enalapril
* Drug: matching placebo sacubitril/valsartan (LCZ696)
* Drug: matching placebo enalapril


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enalapril<br>Double blind treatment epoch: Patients randomized to this arm received 1 tablet of enalapril and 1 tablet of matching placebo sacubitril/valsartan twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 2.5 mg enalapril BID). Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 (i.e. 10 mg enalapril BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level. Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on enalapril Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1 of sacubitril/valsartan. Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 of sacubitril/valsartan. Patients not tolerating dose escalation could have been titrated down to next lower dose level. | Drug: sacubitril/valsartan (LCZ696)<br>* sacubitril/valsartan tablet taken orally.<br>Drug: enalapril<br>* Enalapril tablet taken orally.<br>Drug: matching placebo sacubitril/valsartan (LCZ696)<br>* matching placebo sacubitril/valsartan tablet taken orally<br>|
| Experimental: Sacubitril/Valsartan<br>Double blind treatment epoch: Patients randomized to this arm received 1 tablet of sacubitril/valsartan and 1 tablet of matching placebo enalapril twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 24/26 mg sacubitril/valsartan BID). Patients may have sequentially been up-titrated to achieve desired dose of Dose Level 3 (i.e. 97/103 mg sacubitril/valsartan BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level. Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1. Patients may sequentially have been up-titrated to achieve desired dose of Dose Level 3. Patients not tolerating dose escalation could have been titrated down to next lower dose level. | Drug: sacubitril/valsartan (LCZ696)<br>* sacubitril/valsartan tablet taken orally.<br>Drug: matching placebo enalapril<br>* matching placebo enalapril tablet taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline, Week 1 | 
| 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). | Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16 | 
| 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). | Baseline, Week 8 | 
| 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). | Baseline, Week 1 | 
| 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). | Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, 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, HReEF, Physical Activity, Actigraphy, Home sleep test, wake