randOmized stUdy Using acceleromeTry to Compare Sacubitril/valsarTan and Enalapril in Patients With Heart Failure

Study Overview
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Brief Summary
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The purpose of this randomized, actively controlled, double-blind study with prospective data collection was to assess differences between sacubitril/valsartan versus enalapril in increasing exercise capacity and non-sedentary physical activity in HFrEF patients. Physical activity was assessed by the 6 minute walk test, and daily physical activity was continuously measured by means of a wrist-worn accelerometry device from 2 weeks before until 12 weeks after start of study therapy (sacubitril/valsartan or enalapril).

Official Title
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A Multi-center, Prospective, Randomized, Double-blind Study to Assess the Impact of Sacubitril/Valsartan vs. Enalapril on Daily Physical Activity Using a Wrist Worn Actigraphy Device in Adult Chronic Heart Failure Patients

Conditions
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Chronic Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: LCZ696 (Sacubitril/Valsartan)
* Drug: Placebo of LCZ696 (Sacubitril/Valsartan)
* Drug: Enalapril
* Drug: Placebo of Enalapril


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Written informed consent obtained before any study assessment is performed. Ambulatory ≥ 18 years of age with a diagnosis of chronic symptomatic HF (NYHA class ≥ II) with reduced ejection fraction, defined as known LVEF ≤ 40% AND one of the following two criteria: Plasma NT-proBNP level of ≥ 300 pg/mL or BNP ≥ 100 pg/mL (measurement may be recorded no longer than past 12 months) OR Confirmation of a heart failure hospitalization last 12 months. Patients must be on stable HF medication for at least 4 weeks prior to Week - 2, where the minimal daily dose of current evidence based therapies is equivalent to at least 2.5 mg/d enalapril Willingness to wear the accelerometer wristband continuously for the duration of the trial. Patients must be living in a setting, allowing them to move about freely and where they are primarily self-responsible for scheduling their sleep and daily activities. Key Exclusion Criteria: History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar chemical classes Use of sacubitril/valsartan prior to week - 2. Bedridden patients, or patients with significantly impaired/limited physical activity and/or fatigue due to medical conditions other than HF, such as, but not limited to angina (chest pain at exertion), arthritis, gout, peripheral artery occlusive disease, obstructive or restrictive lung disease, malignant disease, neurological disorders (e.g. Parkinson's or Alzheimer's disease, central and peripheral neuroinflammatory and -degenerative disorders or functional central nervous lesions due to hemodynamic or traumatic incidents), injuries (incl. diabetic foot ulcers) or missing limbs Patients with palsy, tremor or rigor affecting the non-dominant arm. Patients with any skin or other condition of the non-dominant arm that would limit the ability to wear the actigraphy device continuously (24h/day) over 14 weeks. Patients fully depending on a mobility support system, e.g. wheelchair, scooter or walker. Patients are allowed to use a cane as long as this is not used with the non-dominant arm.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCZ696 (Sacubitril/Valsartan)<br>After randomization, patients in this arm received LCZ696 (Sacubitril/Valsartan) twice daily and matching placebo of Enalapril depending on the patient's previous ACEI/ARB dose (enalapril equivalent dose) for 2 weeks. Patients could start study medication at dose level 1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ) or matching placebo bid. After 2 weeks (visit 3) the doses were up-titrated: patients, who started on dose level 2 or 2a received the target dose of study medication (level 3) at this point. After another 2 weeks (visit 4) all patients were to achieve the target dose of 97 mg/103 mg bid LCZ696(sacubitril/valsartan) and matching placebo, provided no safety and tolerability issues arised during uptitration. | Drug: LCZ696 (Sacubitril/Valsartan)<br>* LCZ696 (sacubitril/valsartan) was available in 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets<br>* Other names: LCZ696;Drug: Placebo of Enalapril<br>* Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets<br>* Other names: Placebo;|
| Active Comparator: Enalapril<br>After randomization, patients in this arm received Enalapril twice daily and matching placebo of LCZ696 (Sacubitril/Valsartan) depending on the patient's previous ACEI/ARB for 2 weeks. Patients could start study medication at dose level 1 or 2a or matching placebo bid. After 2 weeks (visit 3) the doses were up-titrated: patients, who started on dose level 2 or 2a received the target dose of study medication (level 3) at this point. After another 2 weeks (visit 4) all patients were to achieve the target dose of 10 mg bid enalapril and matching placebo, provided no safety and tolerability issues arised during uptitration | Drug: Placebo of LCZ696 (Sacubitril/Valsartan)<br>* Placebo of LCZ696 (sacubitril/valsartan) was available to match 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets<br>* Other names: Placebo;Drug: Enalapril<br>* Enalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) | The impact of LCZ696 (Sacubitril/Valsartan) and Enalapril on functional exercise capacity was measured by the Six Minute Walk Test at 12 weeks. The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. | Baseline, Week 12 | 
| Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) | Non-sedentary physical activity is defined as >= 178.50 activity counts per minute; the average number of minutes per day spent in non-sedentary physical activity is being calculated over 14 days before randomization (baseline i.e. week -2 to week 0) and the last 14 days of treatment (i.e. week 10 to week 12). | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS | The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group. | Baseline, Week 12 | 
| Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Subset Without AE/SAE | The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group. | Baseline, Week 12 | 
| Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS | The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group in a subset of patients with baseline six-minute walk distance equal to or less than 300 meters. | Baseline, Week 12 | 
| Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Subset Without AE/SAE | The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group in a subset of patients with baseline six-minute walk distance equal to or less than 300 meters. | Baseline, Week 12 | 
| Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS | The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group in a subset of patients with baseline six-minute walk distance from 100 to 450 meters. | Baseline, Week 12 | 
| Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Subset Without AE/SAE | The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group in a subset of patients with baseline six-minute walk distance from 100 to 450 meters. | Baseline, Week 12 | 
| Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 | The impact of LCZ696 (Sacubitril/Valsartan) and Enalapril on functional exercise capacity was measured by the Six Minute Walk Test at Weeks 4 and 8. The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. | Baseline, Week 4 and Week 8 | 
| Number and Percentage of Participants Who Show Increased Levels (>= 10% Increase) of Non Sedentary Daytime Physical Activity at Week 12 Compared to Baseline | Non-sedentary physical activity is defined as >= 178.50 activity counts per minute; the average number of minutes per day spent in non-sedentary physical activity will be calculated over 14 days before randomization (baseline) and the last 14 days of treatment (i.e week 10 to week 12) | Baseline, Week 12 | 
| Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 | The Patient Global Assessment (PGA) is a self-reported tool to assess the patients' subjective rating of their disease activity widely used in HF research. The patients are asked to report functioning or response to an intervention by rating their current condition compared to their pre-intervention condition on a numerical scale: 1) much improved 2) moderately improved 3) a little improved 4) unchanged 5) a little worse 6) moderately worse or 7) much worse. | Week 4, Week 8, Week 12 | 
| Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) | The Patient Global Assessment (PGA) is a self-reported tool to assess the patients' subjective rating of their disease activity widely used in HF research. The patients are asked to report functioning or response to an intervention by rating their current condition compared to their pre-intervention condition on a numerical scale: 1) much improved 2) moderately improved 3) a little improved 4) unchanged 5) a little worse 6) moderately worse or 7) much worse. Patients with improved symptoms were categorized as: Improvement, Is unchanged, Gets worse or Missing. | Week 4, Week 8, Week 12 | 
| Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals | Non-sedentary physical activity is defined as >= 178.50 activity counts per minute; Mean daily non-sedentary daytime physical activity were being calculated over weekly and compared to before the inclusion. | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | 
| Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals | Non-sedentary physical activity is defined as >= 178.50 activity counts per minute; Mean daily non-sedentary daytime physical activity were being calculated over two-weekly intervals and compared to before the inclusion. | Baseline, Weeks 0 to 2, Weeks 2 to 4, Weeks 4 to 6, Weeks 6 to 8, Weeks 8 to 10, Weeks 10 to 12 | 
| Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity | The average number of minutes per day spent in light non-sedentary physical activity was being calculated over 7 day epochs. Non-sedentary physical activity is defined as >= 178.5 activity counts per minute and light physical activity is defined as 178.5 - 565.5 counts per minute. | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | 
| Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity | The average number of minutes per day spent in moderate to vigorous non-sedentary physical activity was being calculated over 7 day epochs. Non-sedentary physical activity is defined as >= 178.5 activity counts per minute and moderate-to-vigorous activity is defined as > 565.5 counts per minute. | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | 
| Total Weekly Time Spent in Non-sedentary Daytime Physical Activity | Non-sedentary physical activity is defined as >= 178.5 activity counts per minute; The total time spent in non-sedentary physical activity was being calculated for each patient in weekly intervals and the temporal course for each patient was assessed. | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | 
| Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity | Light non-sedentary daytime physical activity is defined as between 178.5 - 565.5 counts per minute; The time spent in light non-sedentary physical activity was being calculated for each patient in weekly intervals and the temporal course for each patient was assessed. | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | 
| Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity | Moderate-to-vigorous non-sedentary physical activity is defined as > 565.5 counts per minute. The total time spent in moderate-to-vigorous non-sedentary physical activity was being calculated for each patient in weekly intervals and the temporal course for each patient was assessed. | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | 
| Change From Baseline in Peak Six Minutes of Daytime Physical Activity | The peak 6 min walk (M6min) is a parameter derived by validated algorithms of the software that are used to preprocess actigraphy data. The parameter reflected the peak 6 minutes of day time physical activity. The mean daily 6-minute walking test was being calculated over 14 day intervals. | Baseline, Week 2, Week 4, Week 6, Week 8 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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actigraphy, sleep, heart failure, reduced ejection fraction, randomized controlled trial, accelerometry, sacubitril/valsartan, enalapril, physical activity