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Rationale and study design ofOUTSTEP-HF: a randomised controlled study to assess the effect of sacubitril/valsartan and enalapril on physical activity measured by accelerometry in patients with heart failure with reduced ejection fraction

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Rationale and study design ofOUTSTEP-HF: a

randomised controlled study to assess the effect

of sacubitril/valsartan and enalapril on physical

activity measured by accelerometry in patients

with heart failure with reduced ejection fraction

Frank Edelmann, Tiny Jaarsma, Josep Comin-Colet, Jessica Schorr, Laurent

Ecochard, Rizwan I Hussain and Massimo F. Piepoli

The self-archived postprint version of this journal article is available at Linköping

University Institutional Repository (DiVA):

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-168538

N.B.: When citing this work, cite the original publication.

Edelmann, F., Jaarsma, T., Comin-Colet, J., Schorr, J., Ecochard, L., Hussain, R. I, Piepoli, M. F., (2020), Rationale and study design ofOUTSTEP-HF: a randomised controlled study to assess the effect of sacubitril/valsartan and enalapril on physical activity measured by accelerometry in patients with heart failure with reduced ejection fraction, European Journal of Heart Failure.

https://doi.org/10.1002/ejhf.1919

Original publication available at:

https://doi.org/10.1002/ejhf.1919

Copyright: Oxford University Press (OUP)

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Rationale and Study Design of OUTSTEP-HF: A Randomized Controlled Study to Assess the Effect of Sacubitril/Valsartan and Enalapril on Physical Activity measured by Accelerometry in Patients with Heart Failure with Reduced Ejection Fraction

Frank Edelmann1,2, Tiny Jaarsma3, Josep Comin-Colet4, Jessica Schorr5, Laurent Ecochard6, Rizwan I.

Hussain6 & Massimo F. Piepoli7,8*.

1 Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin,

Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany

2 German Centre for Cardiovascular Research (DZHK), partner site Berlin

3Division of Nursing Science, Department of Health, Medicine and Caring Sciences , Linköping

University, Linköping, Sweden

4Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital and

Biomedical Research Institute (IDIBELL), University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain

5Novartis Pharma GmbH, Nürnberg, Germany

6Novartis Pharma AG, Basel, Switzerland

7Heart Failure Unit, Cardiology Department, G. Da Saliceto Polichirurgico Hospital, Piacenza, University

of Parma, and Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy

*Corresponding author:

Prof. Massimo Piepoli

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G da Saliceto Hospital,

Piacenza, I-29121, Italy

Email:

m.piepoli@ausl.pc.it

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Abstract:

Aim: In PARADIGM-HF, sacubitril/valsartan demonstrated superiority to enalapril in reducing mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several patient-centred outcomes like improved physical activity and quality of life (QoL) have been emphasised as important therapy goals in HF management. OUTSTEP-HF has been designed to evaluate the effects of sacubitril/valsartan compared with enalapril on non-sedentary daytime physical activity in patients with HFrEF.

Methods: OUTSTEP-HF is a randomised, actively controlled, double-blind, double-dummy study that plans to enrol 600 ambulatory patients with symptomatic HFrEF in 19 European countries. Patients will be randomised 1:1 to receive sacubitril/valsartan 97/103 mg twice-daily (bid) or enalapril 10 mg bid. The primary objective of the study was to assess changes from baseline (week 0) to week 12 in exercise capacity measured by 6MWT and in daily non-sedentary daytime activity Physical activity and objective sleep parameters will be measured by accelerometry using a wrist worn device, worn continuously from screening (Week −2) until the end-of-study (Week 12). As a co-primary outcome, changes from baseline in sub-maximal exercise capacity will be assessed by the 6-minute walking test. Patient- and physician-reported questionnaires will be used to assess QoL, changes in signs and symptoms of HF and sleep parameters.

Conclusion: OUTSTEP-HF will be the largest randomized trial in HF to date to use non-invasive accelerometry to assess whether treatment with sacubitril/valsartan improves patients’ daily physical activity and exercise capacity compared with enalapril.

Keywords: physical activity, exercise, accelerometry, heart failure with reduced ejection fraction, quality of life, sleep, sacubitril/valsartan

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Introduction

Heart failure (HF) is a leading cause of mortality, morbidity and hospitalisations globally (1). In Europe, HF prevalence varies between 1-2%, but rises to >10% in the elderly (age >85 years) population (2). Chronic HF is a debilitating and progressive disorder that develops from structural or functional anomalies of the heart. This impacts the ability of the heart to supply adequate blood to meet the body’s metabolic demands resulting in dyspnoea and fatigue, the cardinal symptoms of HF (3). Hence, patients with HF have a reduced exercise tolerance leading to diminished physical activity (PA) (4-6) and poor prognosis. Improving PA, therefore, has been identified as an important therapy goal for the treatment of patients with HF to reduce the risk of HF hospitalization (7, 8).

PA is one of the integral functional and psychosocial components of quality of life (QoL) and reduced PA limits day-to-day social activities of patients with HF, adversely affecting QoL (3). Many instruments designed to evaluate QoL in HF patients focus on the physical limitations imposed by HF (9). Compared to other chronic illnesses such as chronic lung disease, arthritis, diabetes, hypertension or angina, patients with HF with reduced ejection fraction (HFrEF) reportedly have lower QoL (10, 11), which is associated with higher rates of hospitalisations and mortality (12, 13). Hence, from the

perspective of a patient with HF, a clinically meaningful improvement in functional capacity and QoL is perhaps more important than living longer, with some patients willing to trade the mortality or morbidity benefits of a therapy for an improved QoL (14). This fact underlines the increasing relevance of PA and QoL as endpoints in clinical studies and as treatment goals in HF management.

The armamentarium of pharmacotherapies to reduce mortality and morbidity in patients with HFrEF has rapidly expanded in the past three decades with many also improving exercise capacity. However, only few pharmacotherapies have been shown to improve patients’ QoL and symptom burden. Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) (15), is the most recent addition to the HFrEF pharmacotherapy owing to its superiority over the angiotensin converting

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enzyme inhibitor (ACEI), enalapril, in reducing mortality and morbidity, as demonstrated in the pivotal PARADIGM-HF study (3, 15). Evidence from PARADIGM-HF and real-world observational studies suggest that sacubitril/valsartan improves QoL in patients with HFrEF (as determined by Kansas City Cardiomyopathy Questionnaire [KCCQ] scores) (15-17). However,

there is limited evidence on effects

of sacubitril/valsartan on physical activity.

In this manuscript, we describe the rationale and design of OUTSTEP-HF (randOmized stUdy using acceleromeTry to compare Sacubitril/valsarTan and Enalapril in Patients with Heart Failure). This study aims to evaluate the effects of sacubitril/valsartan compared with enalapril on non-sedentary daytime PA in patients with HFrEF measured by accelerometry to capture continuous PA and six-minute walk test (6MWT).

Study Design

Study population

The study enrolled adult (age ≥18 years) patients with HF (NYHA class II-IV) and reduced ejection fraction (LVEF ≤40%), with elevated natriuretic peptides managed by a primary care physician, office-based cardiologist or in HF outpatient clinics providing a written consent and fulfilling all the criteria for inclusion and none of the exclusion criteria (Table 1).

Study design

OUTSTEP-HF is a multi-centre, randomised, active-controlled, double-blind, double-dummy study (

ClinicalTrials.gov number, NCT02900378

) which recruited patients in 19 European countries (Figure 1). The trial was designed and executed in accordance with the International Conference on Harmonization tripartite guidelines (ICH E6(R2) Integrated Addendum) for good clinical practice and will be conducted in accordance with the ethical principles laid down in the Declaration of Helsinki.

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The study comprises of six visits over 14 weeks with an initial 2 weeks of screening and baseline assessments, followed by 12 weeks of randomised double-blind treatment period (Figure 2). Patients were randomised 1:1

using the Interactive Response Technology (IRT) to one of the treatment arms.

Actigraphy, a non-invasive method for monitoring PA using accelerometry, will be performed during the entire duration of the study by means of a wrist-worn device. At Visit 1 (Week −2), patients fulfilling all eligibility criteria will receive the actigraphy device. The device will be worn continuously, starting two weeks prior to randomisation, in order to obtain an individual baseline value for each patient, until the end of the treatment period (12 weeks). Device non-wear time was defined as 120 minutes or more of

continues zero activity. Additionally, at least 10 hours of activity recordings in day are needed for a valid measurement of daily non-sedentary daytime activity.

During baseline, the patients will continue their HF medications (including ACEI or angiotensin II receptor blocker [ARB]) along with other concomitant therapies. At Visit 2 (Week 0), patients will be randomised to receive either sacubitril/valsartan or enalapril. During the double-blind treatment, patients will continue their background therapies for HF and CV disease and symptomatic treatment (such as diuretics) with the exception of ACEIs/ARBs, which will be replaced by the study drugs after a washout period of 36 hours. Treatment will be initiated based on the previous ACEI/ ARB dose (beginning from enalapril 2.5 mg bid or sacubitril/valsartan 24/26 mg bid; Table 2) and up-titrated to target doses by Week 4 (enalapril 10 mg bid or sacubitril/valsartan 97/103 mg bid), in the absence of any safety/tolerability issues. The details of the assessments carried out at each study visit are depicted in Supplementary Figure 1.

Study objectives

The primary objectives of the study was to assess changes from baseline (week 0) to week 12 in exercise capacity measured by 6MWT and in daily non-sedentary daytime activity (defined as >178.5

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activity counts/minute assessed by accelerometry), between baseline and after 12 weeks of treatment with sacubitril/valsartan versus enalapril treated patients.

The importance of 6MWT was increased from a secondary endpoint to a co-primary endpoint along with the actigraphy-based endpoint after recruitment was complete but before database lock and unblinding. 6MWT is commonly used to assess physical activity in cardiopulmonary diseases, is considered as validated endpoint in HF studies and is considered by the CHMP to be reliable and preferred method of elucidating functional capacity in patients with HF whereas accelerometry is currently not validated in HF. As the 6MWT was already accounted for when calculating the initial sample size while planning the study, the changes implemented did affect neither the study sample size nor the remaining of the trial conduct.

The key secondary and exploratory objectives are shown in Table 3.

Accelerometry (actigraphy) based monitoring of physical activity

Actigraphy was performed by using a wrist-worn device that collects data on activity by means of tri-axial accelerometry. The lightweight, water-resistant, medical-grade device (MotionWatch8®,

CamNtech, Cambridge, UK) was worn continuously on the non-dominant arm of the patient for the entire duration of the study and will collect data on movement continuously in 30-second bins. The raw

accelerometry data collected will be analysed using dedicated software (MotionWare, CamNtech, Cambridge, UK) to derive objective actigraphy measures. Data from Week −2 to Week 0 will be used to define the baseline average minutes spent per day in daytime non-sedentary PA for individual patients.

Based on the accelerometry data for each 30-second bin, activity counts for each minute of each day will be generated. Higher data counts reflect higher PA. Based on cut-off values for the elderly

population(18), PA will be categorised as - sedentary (<178.5 activity counts/minute) - light (178.5-565.5 activity counts/minute)

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- moderate-to-vigorous (>565.5 activity counts/minute)

The amount of time that patients spent in a given activity intensity category will be recorded and will form the basis for all accelerometry-derived endpoints. The accelerometry data will be integrated in two-weekly bins (or two-weekly for certain endpoints) to obtain stable data for each patient and to minimise the effects of individual extreme variations in activity levels. The long-term recordings of activity counts will also be used to analyse circadian rhythm with the non parametric circadian rhythm analysis (NPCRA) by using the MotionWare software (19).

6-minute walking test (6MWT)

6MWT is a validated endpoint to clinically assess the patients’ physical activity in HF

studies.(20)

Patients were instructed to walk down a long corridor at their own pace, attempting to cover as much distance as possible within 6 minutes. At the end of the 6-minute duration, the distance walked was calculated and recorded (21) along with any symptoms.

QoL and patient-centred outcome assessments

Patient global assessment (PGA) assessment will be performed by patients at Weeks 4, 8, and 12. PGA is a self-reported tool to assess patients’ subjective rating of their disease condition. The patients will be asked to report their response to an intervention by rating their current condition compared to their pre-intervention condition on a numerical scale of 1 (much improved) to 7 (much worse) (22). The Pittsburgh Sleep Quality Index (PSQI) evaluates subjective sleep quality, comprising a 19-item questionnaire assessing subjective rating of 7 components of sleep (quality, latency, duration, habitual efficiency, disturbance, use of sleep medication and daytime dysfunction) (23). The patients are asked to fill the questionnaire retrospectively, surveying sleep quality over the previous month at Week -2, baseline (randomization) and at Weeks 4, 8, and 12.

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In addition, patients will also complete the Short-Form 12-item Health Survey (SF-12) and the EuroQoL five-dimensional (EQ-5D) questionnaires at baseline and at Weeks 4, 8 and 12 to assess their QoL. The physician global assessment (PhyGA) is a tool where physicians rate their patient’s condition on a continuous numerical scale ranging from 1 (markedly worse) to 7 (markedly improved) (24) and will be performed at weeks 4, 8, and 12 by the same investigator throughout the study.

Safety and tolerability

Safety assessments consisted of collecting all AEs, serious adverse events (SAEs), with their severity and relationship to study drug, and pregnancies. Patients will be monitored at each visit for AEs and serious AEs (SAEs) including hyperkalaemia, symptomatic hypotension, increase in serum

creatinine, decreased renal function, worsening hepatic function and angioedema. Patients who cannot tolerate the target dose of study drugs will be down-titrated to lower doses, or study drugs will be discontinued at the investigator’s discretion.

Statistical considerations

Sample size: A 10% change in exercise tolerance has been considered predictive of effectiveness of physical training programme in HFrEF (6). Assuming a mean baseline value of 200-230 minutes/day of activity time for both groups, a difference of at least 20 minutes of non-sedentary PA per day in the sacubitril/valsartan group compared with enalapril group would be considered clinically relevant (25). A two-sided test (using the t-test model with α = 0.05 and 90% power at Δ = 20 minutes/day) indicates a sample size of 259 patients per treatment group. In order to account for dropout patients, the study will recruit 300 patients per treatment arm, i.e. 600 patients in total. For the 6MWT, a two-sided test with α=0.05 and 90% power would need a sample size of 224 patients for a between-treatment difference of 35 meters (21).

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Statistical hypothesis: The primary hypothesis to be rejected for the accelerometry based co-primary endpoint is that the change in mean non-sedentary daytime activity between baseline and ‘end-of-study’ with sacubitril/valsartan treatment is equal to the change with enalapril treatment. Similarly, for the co-primary endpoint of 6MWT, the co-primary hypothesis to be rejected is that 6MWT between baseline and end-of-study with sacubitril/valsartan treatment is equal to the change with enalapril treatment.

Handling of missing data/censoring/discontinuations: For patients who drop out prematurely and/or did not have a valid measurement of mean-daily non-sedentary daytime activity between weeks 10-12, a multiple imputation approach will be used for the primary analysis. A last-observation-carried-forward (LOCF) imputation method will be also be carried out where the last available value of non-sedentary daytime activity over two weeks under treatment will be used for the primary analysis in a sensitivity analysis. No imputation of missing data of 6MWT efficacy variable will be performed. Secondary and exploratory endpoints will be imputed by using the LOCF approach.

The comparison of treatment groups were carried out by an analysis of covariance (ANCOVA) model with treatment and baseline New York Heart Association (NYHA) class (NYHA II vs. III/IV) as factors and the baseline value as covariate. The two-sided 97.5% confidence interval (CI) and p-values will be reported at α=0.025 considering the two co-primary endpoints and using Bonferroni correction for multiple comparisons. Key secondary variables will be analysed by applying a logistic regression model with treatment and baseline NYHA class as fixed factors and the baseline value as covariate, and the odds ratio (95% CI) will be reported. All other secondary and exploratory efficacy variables will be analysed descriptively using statistics for continuous and categorical data.

Results

A total of 764 patients were screened and 621 were randomized 1:1 to receive either sacubitril/valsartan 200 mg BID (N=310) or enalapril 10 mg BID (N=311).

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Baseline characteristics of patients enrolled in OUTSTEP-HF

The baseline and clinical characteristics of the patients are summarized in Table 4. The mean age of the overall population was 66.9 (SD 10.7) years with nearly 60% of the patients being elderly (aged ≥65 years). Mean BMI was 29.3 (SD 4.7) kg/m2 and p

rimary aetiology of HF was mainly ischaemic

(56.7%)

(Table 4). Hypertension (67.2%), dyslipidaemia (61.6%), CAD (43.1%), and AF (43.5%) were the common comorbidities (Table 4).

Patients enrolled in OUSTEP-HF were largely similar to those randomized in the PARADIGM-HF trial (26) (Table 4). However, compared with PARADIGM-HF a higher proportion of patients in OUTSTEP-HF belonged to NYHA class III (due to the study design), had AF/flutter, and were older (Table 4). Patients in both the trials were well treated with disease-modifying HF therapies (Table 4)

Discussion

Rationale

Over the past few decades, several clinical studies have demonstrated the benefit of various disease-modifying therapies in reducing mortality and/or hospitalisation burden of HF. These ‘hard-endpoints’ are considered to be the most relevant for evaluation of new therapies (27). However, the recent European Society of Cardiology (ESC) guidelinesemphasize that the therapeutic goal in HF should not be limited to prolonging survival but also improving QoL (3). The progressive nature of HF and its symptomatic burden affects the physical and psychosocial aspects of QoL of patients with HF. Hence, several ‘patient-centred’ outcomes such as improved exercise ability/capacity and QoL that provide insights into the efficacy of a therapy from the patients’ perspective are increasingly being emphasised as ‘soft endpoints’ in clinical trials and are being recognised as important goals in HF management (27). While many disease-modifying therapies improve exercise capacity, few have been shown to significantly improve patient’s QoL.

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In the pivotal PARADIGM-HF study, sacubitril/valsartan was superior to enalapril in reducing mortality, HF hospitalisation and slowing clinical progression in patients with HFrEF, and improved QoL (assessed by KCCQ scores) (15, 16). However, the timing of baseline QoL assessments after enalapril and sacubitril/valsartan run-in phase in PARADIGM-HF may have limited the assessments of clinically meaningful improvements in QoL. Recent evidence from the CHAMP-HF observational study suggests that sacubitril/valsartan treatment is associated with early and robust improvements in QoL as assessed by KCCQ-OS, including physical limitation scores (17). These observations suggest that sacubitril/valsartan therapy might be beneficial in improving HF symptoms, especially exertional symptoms, which could potentially translate into increased voluntary PA and improved QoL. OUTSTEP-HF is the first study that will evaluate the effects of sacubitril/valsartan on daily PA in patients with HFrEF and will generate further data regarding the impact of sacubitril/valsartan therapy on QoL of these patients.

The inverse association between physical fitness and the incidence of cardiovascular disease and mortality(28) has been well documented. Physical inactivity is associated with up to 2-fold greater risk of all-cause and cardiac deaths (4) and increasing PA and exercise capacity in patients with HF is positively correlated with improved symptoms, QoL and clinical outcomes (5, 29-32). The current ESC guidelines recognise PA as a modifiable lifestyle factor for prevention of HF and increasing exercise capacity has been recognised as an integral component of managing symptoms in patients with HF (8). Even a 10-minute increase in daily PA in patients with HF has been shown to have a beneficial impact on mortality and hospitalisation risk (33). Moderate PA of at least 30 min/day or 150 min/week has therefore been recommended for patients with HF (8). As PA can be of value as a prognostic indicator of HF, there is a growing need to recognise PA as an endpoint in clinical studies.

PA can be assessed by a plethora of methods. Patient-reported activity questionnaires, diaries/logs, and/or supervised exercise trainings and tests, (such as the 6MWT) or various treadmill cardiopulmonary exercise tests (CPET) with peak O2 consumption evaluation are commonly used to

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personal bias, are mostly qualitative, have poor patient compliance and may not necessarily reflect the full effects of a therapy on a patient’s daily PA (34).

Wearable activity-tracking devices are a promising alternative to conventional methods of assessing daily PA and to promote exercise participation in patients with HF. These accelerometer-based devices can continuously track and quantify multiple aspects of daily PA including duration and

frequency of activity, walking (distance covered, number of steps, speed etc.), duration of sedentary and active behaviours and circadian patterns of activity and sleep patterns (34). The actigraphy device used in the current study (MotionWatch8®) is a small, lightweight, water-resistant device with long battery life

and is unobtrusive. It provides objective and continuous assessment of daily PA of patients over a long period of time, reflecting the effect of a therapy on PA more accurately than traditional subjective and/or clinical methods (34).

PA assessed by accelerometers in patients with HF correlates well with traditional exercise tests such as the 6MWT(35) and CPET in addition to exercise capacity (as determined by peak oxygen consumption) and is predictive of disease severity, hospitalisation and mortality (31, 33). By using accelerometer-based tracking, it has been shown that HF patients with anergia are less active than those without (36),and that many patients with HF do not engage in PA or only engage in light activity and, hence have both poor prognosis and poor QoL (37). These observations demonstrate the utility of wearable activity trackers in evaluating clinical status and its possible implications for therapeutic intervention in patients with HF.

Several key features of the OUTSTEP-HF study and its design merit further mention. The study aims to evaluate the short-term (12 weeks) effects of pharmacotherapy on physical activity in patients with HFrEF. Due to the proven long-term superiority of sacubitril/valsartan over enalapril, the duration of the double-blind treatment period (12 weeks) was envisaged as sufficient to allow for up-titration and maintenance of a stable tolerated dose of study drug while being short enough to mitigate the risks of withholding the superior therapy. OUTSTEP-HF employs a novel actigraphy-based approach to

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6MWT in a large population of patients with HFrEF across multiple centres in Europe to compare the effects of pharmacotherapies on PA over a 14-week study period. The study harnesses the advantages of wearable devices to confer flexibility to patients to determine the routine activity patterns in their day-to-day living. This is essential since many activity and exercise opportunities exist in a day-to-day, and the physical activities associated with routine daily living have also been shown to be effective in improving outcomes (34).

Further, several elements in this study are designed to complement actigraphy-derived data with conventional evaluations of PA and QoL, such as the 6MWT. 6MWT is a standardized, frequently used and well-tolerated test for functional evaluation of the HF patients’ submaximal exercise capacity and exercise tolerance and has important prognostic value in these patients. Actigraphy-derived data and ratings from self- and physician-reported questionnaires can also aid in examining the potential correlation between improved PA and QoL.

Ratings from several self-assessment questionnaires (PGA, SF-12 and EQ-5D) in addition to physician’s assessment (PhyGA) take into account multiple factors that influence QoL. Generic

instruments like SF-12 and EQ-5D and patient reported questionnaires (like PGA) can provide valuable insights into the actual impact of the therapy, including safety and efficacy aspects that influence QoL (38). Although actigraphy allows for objective measurements of PA, this study is double-blinded to avoid bias due to treatment expectations by patients and to reduce subjective bias in ratings of self-assessment and physician assessment questionnaires (PGA, PSQI, PhyGA, SF-12 and EQ-5D).

Both daily activity patterns and sleep profiles are highly individualistic. Therefore, it is essential to obtain a stable baseline activity and to monitor activity profiles continuously. In OUTSTEP-HF, patients will wear the actigraphy device continuously (24-hours a day) throughout the 14-week study to ensure that stable data is obtained for each patient and to minimise the effects of individual extremes in activity patterns.

Limitations: Despite its several advantages over conventional methods, few challenges exist in using

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not well suited for accurate determination of energy expenditure, and certain activities such as cycling and walking uphill are not accurately measured by actigraphy. Gait speed and physical activity of an elderly population, such as that enrolled in the current study, could be lower. The thresholds used for defining sedentary and non-sedentary activities in OUTSTEP-HF, however, were derived from an elderly, but healthy, population (18). Also, this device has not been validated in HF patients and, thus, the cut-off values specific to the HF population are not available. However, since the current study is designed to measure the relative changes from baseline activity in each patient, and each patient serves as his/her own control, absolute levels of PA may be considered less important. In addition, as accelerometry is currently not validated in HF, the importance of 6MWT was increased from a secondary endpoint to a co-primary endpoint along with actigraphy-based endpoint. 6MWT is a validated endpoint in HF studies and is a preferred method for evaluating functional capacity in patients with HF. Further, the study was designed to determine improvements in voluntary physical activity attributable to amelioration of HF symptoms. It is plausible that some patients accustomed to a largely sedentary lifestyle may not increase their physical activity despite improvements in their symptoms.

In summary, OUTSTEP-HF is the largest HF randomised clinical trial, to date, employing a state-of-the-art accelerometry-based approach along with the 6MWT to evaluate the effect of

sacubitril/valsartan compared to enalapril on daily PA in patients with HFrEF. In addition, this study will aid in the assessment of whether amelioration of exertional symptoms of HF by sacubitril/valsartan results in improvements in daily PA of patients with HFrEF.

Acknowledgements

The authors acknowledge Nagabhushana Ananthamurthy, Roohi Chopra (Scientific Services, Novartis Healthcare Pvt. Ltd, Hyderabad) and Theresa Reape (Novartis Ireland Limited, Dublin) for providing medical writing and editorial support.

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Funding

This study is sponsored by Novartis Pharma AG.

Conflicts of interest

JS and LE are employees of Novartis Pharma AG. RH was an employee of Novartis Pharma AG during the conduct of this study. JCC has received unrestricted research grants from Novartis and consultancy and honoraria from Novartis. MP has received speaker honorarium, consultancy from Astra Zeneca, Novartis, and Servier. FE has received person fees from Novartis, CVRx, Pfizer, Medtronic, MSD, Bayer, and Resmed, non-financial support from Novartis, personal fees and grant from Boehringer Ingelheim and Servier. TJ has received reimbursement for consultation from Novartis.

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11. Comin-Colet J, Anguita M, Formiga F, Almenar L, Crespo-Leiro MG, Manzano L, Muniz J, Chaves J, de Frutos T, Enjuanes C, researchers V-Ims. Health-related Quality of Life of Patients With Chronic Systolic Heart Failure in Spain: Results of the VIDA-IC Study. Rev Esp Cardiol (Engl Ed). 2016

Mar;69(3):256-271.

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14. Stanek EJ, Oates MB, McGhan WF, Denofrio D, Loh E. Preferences for treatment outcomes in patients with heart failure: symptoms versus survival. J Card Fail. 2000 Sep;6(3):225-232.

15. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, Investigators P-H, Committees. Angiotensin-neprilysin inhibition versus

enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.

16. Lewis EF, Claggett BL, McMurray JJV, Packer M, Lefkowitz MP, Rouleau JL, Liu J, Shi VC, Zile MR, Desai AS, Solomon SD, Swedberg K. Health-Related Quality of Life Outcomes in PARADIGM-HF. Circ

Heart Fail. 2017 Aug;10(8).

17. Khariton Y, Fonarow GC, Arnold SV, Hellkamp A, Nassif ME, Sharma PP, Butler J, Thomas L, Duffy CI, DeVore AD, Albert NM, Patterson JH, Williams FB, McCague K, Spertus JA. Association Between Sacubitril/Valsartan Initiation and Health Status Outcomes in Heart Failure With Reduced Ejection Fraction. JACC Heart Fail. 2019 Nov;7(11):933-941.

18. Landry GJ, Falck RS, Beets MW, Liu-Ambrose T. Measuring physical activity in older adults: calibrating cut-points for the MotionWatch 8((c)). Front Aging Neurosci. 2015;7:165.

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2012;21:218-218.

20. Ferreira JP, Duarte K, Graves TL, Zile MR, Abraham WT, Weaver FA, Lindenfeld J, Zannad F. Natriuretic Peptides, 6-Min Walk Test, and Quality-of-Life Questionnaires as Clinically Meaningful Endpoints in HF Trials. J Am Coll Cardiol. 2016 Dec 20;68(24):2690-2707.

21. Tager T, Hanholz W, Cebola R, Frohlich H, Franke J, Doesch A, Katus HA, Wians FH, Jr., Frankenstein L. Minimal important difference for 6-minute walk test distances among patients with chronic heart failure. Int J Cardiol. 2014 Sep;176(1):94-98.

22. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P, Investigators F-HT. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009 Dec 17;361(25):2436-2448.

23. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

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24. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation. 1996 Dec 01;94(11):2800-2806.

25. Alosco ML, Spitznagel MB, Cohen R, Sweet LH, Hayes SM, Josephson R, Hughes J, Gunstad J. Decreases in daily physical activity predict acute decline in attention and executive function in heart failure. J Card Fail. 2015 Apr;21(4):339-346.

26. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz M, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, Investigators P-HC. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014 Jul;16(7):817-825.

27. Zannad F, Garcia AA, Anker SD, Armstrong PW, Calvo G, Cleland JG, Cohn JN, Dickstein K, Domanski MJ, Ekman I, Filippatos GS, Gheorghiade M, Hernandez AF, Jaarsma T, Koglin J, Konstam M, Kupfer S, Maggioni AP, Mebazaa A, Metra M, Nowack C, Pieske B, Pina IL, Pocock SJ, Ponikowski P, Rosano G, Ruilope LM, Ruschitzka F, Severin T, Solomon S, Stein K, Stockbridge NL, Stough WG,

Swedberg K, Tavazzi L, Voors AA, Wasserman SM, Woehrle H, Zalewski A, McMurray JJ. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail. 2013 Oct;15(10):1082-1094.

28. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y, Yamada N, Sone H. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA. 2009 May

20;301(19):2024-2035.

29. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome. Circulation. 1999 Mar 09;99(9):1173-1182.

30. McKelvie RS. Exercise training in patients with heart failure: clinical outcomes, safety, and indications. Heart Fail Rev. 2008 Feb;13(1):3-11.

31. Swank AM, Horton J, Fleg JL, Fonarow GC, Keteyian S, Goldberg L, Wolfel G, Handberg EM, Bensimhon D, Illiou MC, Vest M, Ewald G, Blackburn G, Leifer E, Cooper L, Kraus WE, Investigators H-A. Modest increase in peak VO2 is related to better clinical outcomes in chronic heart failure patients: results from heart failure and a controlled trial to investigate outcomes of exercise training. Circ Heart

Fail. 2012 Sep 01;5(5):579-585.

32. O'Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, Kraus WE, Kitzman DW, Blumenthal JA, Rendall DS, Miller NH, Fleg JL, Schulman KA, McKelvie RS, Zannad F, Pina IL, Investigators H-A. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. 2009 Apr 08;301(14):1439-1450.

33. Conraads VM, Spruit MA, Braunschweig F, Cowie MR, Tavazzi L, Borggrefe M, Hill MR, Jacobs S, Gerritse B, van Veldhuisen DJ. Physical activity measured with implanted devices predicts patient outcome in chronic heart failure. Circ Heart Fail. 2014 Mar 01;7(2):279-287.

34. Alharbi M, Straiton N, Gallagher R. Harnessing the Potential of Wearable Activity Trackers for Heart Failure Self-Care. Curr Heart Fail Rep. 2017 Feb;14(1):23-29.

35. Howell J, Strong BM, Weisenberg J, Kakade A, Gao Q, Cuddihy P, Delisle S, Kachnowski S, Maurer MS. Maximum daily 6 minutes of activity: an index of functional capacity derived from actigraphy and its application to older adults with heart failure. J Am Geriatr Soc. 2010 May;58(5):931-936.

36. Maurer MS, Cuddihy P, Weisenberg J, Delisle S, Strong BM, Gao Q, Kachnowski S, Howell J. The prevalence and impact of anergia (lack of energy) in subjects with heart failure and its associations with actigraphy. J Card Fail. 2009 Mar;15(2):145-151.

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37. Dontje ML, van der Wal MH, Stolk RP, Brugemann J, Jaarsma T, Wijtvliet PE, van der Schans CP, de Greef MH. Daily physical activity in stable heart failure patients. J Cardiovasc Nurs. 2014 May-Jun;29(3):218-226.

38. Inkrot S, Lainscak M, Edelmann F, Loncar G, Stankovic I, Celic V, Apostolovic S, Tahirovic E, Trippel T, Herrmann-Lingen C, Gelbrich G, Dungen HD. Poor self-rated health predicts mortality in patients with stable chronic heart failure. Eur J Cardiovasc Nurs. 2016 Dec;15(7):504-512.

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FIGURE LEGENDS:

Figure 1: OUTSTEP-HF: Participating countries Figure 2: Study design

1-2 Sacubitril/valsartan or enalapril (double-blind study drugs) will be given at dose levels (up-titration) depending

on pre-study ACEI/ARB doses.

3Pre-study ACEI and/or ARB are replaced by study medication after Visit 2 (randomization). Therefore, a washout

period (WO) of 36 hours is required; it should start 12 hours before Visit 2 (randomisation); the first study treatment intake should be 24 hours after Visit 2.

4All other HF background and CV medications (e.g. beta blockers, MRAs etc.) and symptomatic treatment (e.g.

diuretics) the patient has been taking should remain unchanged throughout the study, if possible and medically justified in the opinion of the investigator.

5Background HF medication per local practice: patients must be on stable HF treatment regimen for at least 4 weeks

prior to Visit 1 (Week -2). After Visit 1, patients shall retain their pre-study HF treatment for another 2 weeks (Week −2 to Week 0) for baseline actigraphy recording.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; HF, heart failure; MRAs, mineralocorticoid receptor antagonists; W, week; WO, washout.

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Inclusion criteria

1. Ambulatory patients with a diagnosis of chronic symptomatic HF (NYHA Class II-IV) with reduced ejection fraction (LVEF≤40%) AND

Plasma NT-proBNP ≥300 pg/mL or BNP ≥100 pg/mL OR A confirmation of HF hospitalisation within the past 12 months.

2. Receiving stable HF medication (ACEI/ARB, beta-blockers, MRAs) for at least 4-weeks prior to screening, with a minimal daily dose of ACEI/ARB equivalent to 2.5 mg/day enalapril (ACEI/ARB doses summarised in Table 2).

3. Willingness to wear the accelerometer continuously for the entire duration of the study.

4. Patients must be living in a setting that allows them to move about freely and where they are primarily self-responsible for scheduling their sleep and daily activities.

Exclusion criteria

1. Use of other investigational drugs within 5 half-lives, or within 30 days of enrolment, whichever is longer. 2. History of hypersensitivity to any of the study drugs or their excipients

3. Prior use of sacubitril/valsartan.

4. Known history of angioedema (i.e. hereditary, idiopathic, related to previous drug use such as ACEI). 5. Bedridden patients, or patients with significantly impaired/limited PA 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, and

neurological disorders (e.g. Parkinson’s or Alzheimer’s disease, central and peripheral neuroinflammatory and degenerative disorders or functional central nervous system lesions due to haemodynamic or traumatic incidents), injuries (including diabetic foot ulcers) or missing limbs.

6. Patients with significant COPD contributing to dyspnoea, or patients whose COPD medication have been altered within 4 weeks prior to screening.

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actigraphy device continuously (24hours a day) over 14 weeks.

9. 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.

10. Patients requiring a dual RAAS blockade (i.e. treatment with both ACEIs and ARBs or concomitant treatment with aliskiren).

11. Patients with acute decompensated HF within 4 weeks of screening, i.e. exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy.

12. Symptomatic hypotension and/or an SBP < 100 mmHg at screening or randomisation.

13. eGFR < 30 mL/min/1.73 m² as calculated by the simplified MDRD formula at screening or randomisation. 14. Serum potassium > 5.4 mmol/L at screening or randomisation.

15. ACS, stroke, TIA, major vascular surgery, PCI or carotid angioplasty within 3 months prior to screening. 16. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 14-week

study duration.

17. Implantation of pacemaker (CRT-P) or -defibrillator (CRT-D) or upgrading of an existing conventional pacemaker or ICD to a CRT device within 3 months prior to screening or such procedure planned within the 14-weeks study duration; patients with an implantation of conventional pacemaker or an ICD or with a revision of a pacemaker or other device electrodes within 1 month prior to screening.

18. Patients with existing or planned/intended heart transplant or VAD.

19. Diagnosis of peripartum- or chemotherapy-induced cardiomyopathy within 12 months prior to screening. 20. Documented untreated ventricular arrhythmia with syncopal episodes within 3 months prior to screening. 21. Symptomatic bradycardia or second or third degree of cardiac electrical conduction without a pacemaker. 22. Haemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation due to

ventricular dilatation.

23. Other haemodynamically significant obstructive lesions of left ventricular outflow, including aortic and sub-aortic stenosis.

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blocker; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association; NT-proBNP, N-terminal pro B-type natriuretic peptide; TIA, transient ischemic attack

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mg/day enalapril)

ACEIs Minimum daily dose ARBs Minimum daily dose

Enalapril 2.5 mg Candesartan 4 mg Benazepril 5 mg Eprosartan 100 mg Captopril 25 mg Irbesartan 37.5 mg Cilazapril 0.625 mg Losartan 12.5 mg Fosinopril 5 mg Olmesartan 2.5 mg Lisinopril 5 mg Telmisartan 10 mg Moexpril 3.75 mg Valsartan 40 mg Perindopril 2 mg Quinapril 5 mg Ramipril 1.25 mg Trandolapril 1 mg Zofenopril 7.5 mg

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Primary Objectives:

• To assess change from baseline (week 0) in exercise capacity assessed by 6MWT at week 12 in sacubitril/valsartan vs. enalapril treated patients

• To assess changes in daily non-sedentary daytime activity between baseline and after 12 weeks of treatment in sacubitril/valsartan vs. enalapril treated patients

Secondary objectives:

• To demonstrate that sacubitril/valsartan is superior in improving exercise capacity as assessed by 6MWT at week 12 in a subset of

o patients with baseline 6-minute walk distance ≥300 meters

o patients with baseline 6-minute walk distance between 100-450 meters

• To assess changes from baseline (week 0) in exercise capacity assessed by means of 6MWT at weeks 4, 8 and 12

• To compare the effects of sacubitril/valsartan vs. enalapril on

o changes in daily non-sedentary daytime activity between baseline and after 12 weeks of treatment

o patients’ symptom progression by means of the PGA questionnaire at weeks 4, 8 and 12

o changes from baseline in mean daily non-sedentary daytime physical activity classified by its intensity at weeks 4. 8 and 12

o non-sedentary daytime physical activity during the treatment period (weeks 0 to 12)

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To compared the effects of sacubitril/valsartan on

• Physicians’ judgement of overall signs and symptoms of HF as assessed by PhyGA questionnaire at weeks 4, 8 and 12

• Short-term changes from baseline of patients’ mental and physical functioning as assessed by SF-12 at weeks 4, 8 and 12

• Change from baseline in patients’ health status as assessed by EQ-5D at weeks 4, 8 and 12

• Changes from baseline is selected objective NPCRA parameters at weeks 4, 8 and 12

• Changes from baseline in subjective sleep quality using PSQI at weeks 4, 8 and 12

M6min is an actigraphy based measure of the peak 6 minutes of physical activity. This parameter derived by

validated algorithms of the software that will be used to pre-process actigraphy data. The mean daily M6min will be calculated over bi-weekly epochs

For all objectives/endpoints assessed by means of actigraphy, the baseline value is obtained over a period of two weeks prior to randomisation, i.e. weeks -2 to week 0, and data will be integrated in two-weekly bins (weekly for some certain endpoints)

EQ-5D, EuroQol five-dimensional; HF, heart failure; NPCRA, non-parametric circadian rhythm analysis; PGA, patient global assessment; PhyGA, physician global assessment; PSQI, Pittsburgh Sleep Quality Index, SF-12, 12-item short-form health survey

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Baseline and demographic characteristics OUTSTEP-HF (N=619) PARADIGM-HF (N=8442) Age, mean (SD) 66.89 (10.74) 64 Female 21.32 22 BMI (kg/m2), mean (SD) 29.32 (4.69) 28 Smoking history Current 15.35 14 Former 45.23 - Never 39.42 -

NYHA class at screening visit

I/II/III/IV 0/52.18/47.17/0.65 5/70/24/1

SBP/DBP at screening visit (mmHg), mean (SD)

126.20 (16.14)/76.06 (10.27) 121/74

Pulse rate at screening visit (bpm), mean (SD)

70.52 (12.26) 72

Ischemic aetiology of HF 56.70 60

Daily non-sedentary daytime activity (minutes), mean (SD)

507.72 (128.37) -

Medical history and treatment

Hypertension 67.21 71

Dyslipidaemia/hyperlipidaemia 61.55 -

MI 45.56 43

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Diabetes 34.41 34

Prior ischemic stroke 7.59 9

PAD 6.79 -

Hospitalization for HF 43.62 63b

Prior medication for HF

ACEI/ARB 97.4 100c

b-blockers 91.6 93

Diuretics 76.6 80

MRA 66.9 60

Data are n (%) unless otherwise specified

ACEI, angiotensin converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BMI, body mass index; CAD, coronary artery disease; DBP, diastolic blood pressure; HF, heart failure; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association, PAD, peripheral artery disease; SBP, systolic blood pressure; SD, standard deviation

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Sleep parameters Description

Total sleep duration The total elapsed time between the ‘fell asleep’ and ‘woke up’ times Sleep onset latency The time between ‘lights out’ and ‘fell asleep’

Sleep fragmentation

Sum of percentages of assumed sleep time categorised as mobile and total number of immobile bouts that are ≤1 min duration (mobile time [% ] + immobile bouts≤1 min [%])

Daytime sleep Periods of inactivity that could be attributed to daytime micro-sleeps derived from adjustable parameter for duration and activity thresholds

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Assessment to be recorded on clinical database; S, assessment to be recorded on source documents only. *Assessments are also to be conducted in patients who withdraw prematurely from the study.

**Optional, if the translations of the questionnaires in local languages are not fully available/approved by the IRB/IEC and health authorities (where required).

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cA full physical examination will be performed at screening; at all other visits, a short examination is to be

performed.

dBefore and during up-titration and as per discretion of the investigator. eOnly if available, not required by the protocol during the visit.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; eGFR, estimated glomerular filtration rate; EOS, end of study; EQ-5D, EuroQol five-dimensional; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B type natriuretic peptide; NYHA, New York Heart Association; PhyGA, physician global assessment; PSQI, Pittsburgh Sleep Quality Index; SF-12, Short-Form 12-Item Health Survey.

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Day (Week) -14 (-2) 1 (0) 14 (2) 28 (4) 56 (8) 84 (12)

Informed consent 

Inclusion/exclusion criteria  

Demography 

Medical history/current medical conditions 

Previous and concomitant drug/non-drug therapy       *

Physical exam S S S S S S S*

Height 

Weight  

Vital signs       *

NYHA class       *

6-minute walking test    

PSQI**     

PhyGA**   

PGA   

SF-12**    

EQ-5D**    

Training patient on use of actigraphy data 

Download actigraphy data from patient’s device    *

Battery change 

Dispense study medication     

Adverse event monitoring      *

Study completion form 

Urine pregnancy test   *

Diagnostic and laboratory evaluations

Potassium       *

AST and ALT       *

Creatinine/eGFR       *

NT-proBNP       *

Haemoglobin       

LVEF       

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Randomization

Screening

ACEI/ARB3 WO

Background HF medication as per local practice

sacubitril/valsartan1

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• Primary endpoint: Change in mean daily non-sedentary daytime activity between baselinea and end-of-study. • Secondary endpoint: Proportion of patients who show increased levels (≥10% increase) of non-sedentary daytime

physical activity at Week 12 compared to baseline.

Secondary objectives: To compare the effects of sacubitril/valsartan vs. enalapril on • Patients’ symptom progression by means of PGA questionnaire at Weeks 4, 8 and 12.

• Dynamics of changes from baselinea in daily non-sedentary daytime physical activity in weekly and bi-weekly intervals. • Changes from baselinea in mean daily non-sedentary daytime physical activity classified by its intensity after Weeks 4, 8

and 12.

• Differences in non-sedentary daytime physical activity during the treatment period (Weeks 0 to 12). • Changes from baselinea on M6minb after Weeks 4, 8 and 12.

• Changes from baseline (week 0) in exercise capacity assessed by means of the 6-minute walking test Exploratory objectives: To compare the effects of sacubitril/valsartan vs. enalapril on

• Physicians’ judgement of overall HF signs and symptoms as measured by the PhyGA questionnaire at Weeks 4, 8 12. • Short-term changes from baseline of patients’ mental and physical functioning as assessed by SF-12 at weeks 4, 8

and 12.

• Change vs. baseline of patients’ health status as assessed by the patients’ self-reported EQ-5D at Weeks 4, 8 and 12. • Changes from baselinea on selected objective sleep parameters

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Randomization

Screening

ACEI/ARB3 :2

Background HF medication as per local practice

sacubitril/valsartan1

References

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