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

Chronic Heart Failure With Reduced Ejection Fraction Clinical Trial

— OUTSTEP-HF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02900378
• Other study ID #: CLCZ696B3301
• Secondary ID: 2016-003085-32
• Status: Completed
• Phase: Phase 3
• Start date: December 20, 2016
• Est. completion date: April 11, 2018

Study information

• Verified date: September 2020
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 621
• Est. completion date: April 11, 2018
• Est. primary completion date: April 11, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Heart Failure With Reduced Ejection Fraction
• Heart Failure

Intervention

Drug:
• LCZ696 (Sacubitril/Valsartan)
LCZ696 (sacubitril/valsartan) was available in 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets
• Placebo of LCZ696 (Sacubitril/Valsartan)
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
• Enalapril
Enalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets
• Placebo of Enalapril
Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Dendermonde
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Geel
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Turnhout
Bulgaria	Novartis Investigative Site	Pleven
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Czechia	Novartis Investigative Site	Brno	Czech Republic
Czechia	Novartis Investigative Site	Chomutov	Czech Republic
Czechia	Novartis Investigative Site	Kolin
Czechia	Novartis Investigative Site	Most	CZE
Czechia	Novartis Investigative Site	Praha 10
Czechia	Novartis Investigative Site	Praha 5
Czechia	Novartis Investigative Site	Svitavy	Czech Republic
Denmark	Novartis Investigative Site	Helsingoer
Denmark	Novartis Investigative Site	Odense C
Denmark	Novartis Investigative Site	Randers
Denmark	Novartis Investigative Site	Roskilde
Denmark	Novartis Investigative Site	Svendborg
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tartu
Finland	Novartis Investigative Site	Hameenlinna
Finland	Novartis Investigative Site	Tampere
France	Novartis Investigative Site	Auxerre
France	Novartis Investigative Site	Clermont-Ferrand Cedex 1
France	Novartis Investigative Site	Metz Tessy
Germany	Novartis Investigative Site	Bad Homburg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Buchholz in der Nordheide
Germany	Novartis Investigative Site	Dietzenbach
Germany	Novartis Investigative Site	Dresden	Sachsen
Germany	Novartis Investigative Site	Elsterwerda
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Halberstadt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hassloch
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Loehne
Germany	Novartis Investigative Site	Mannheim
Germany	Novartis Investigative Site	Muehldorf
Germany	Novartis Investigative Site	Nuremberg
Germany	Novartis Investigative Site	Reinfeld
Germany	Novartis Investigative Site	Schwaebisch Hall
Germany	Novartis Investigative Site	Siegen
Germany	Novartis Investigative Site	Wallerfing
Germany	Novartis Investigative Site	Wedel
Germany	Novartis Investigative Site	Wermsdorf
Greece	Novartis Investigative Site	Alexandroupolis	Evros
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Heraklion Crete
Greece	Novartis Investigative Site	Voula	GR
Iceland	Novartis Investigative Site	Kopavogur
Iceland	Novartis Investigative Site	Reykjavik
Ireland	Novartis Investigative Site	Dublin 7
Latvia	Novartis Investigative Site	Jelgava
Latvia	Novartis Investigative Site	Ogre
Latvia	Novartis Investigative Site	Riga
Latvia	Novartis Investigative Site	Riga
Latvia	Novartis Investigative Site	Riga
Lithuania	Novartis Investigative Site	Kaunas	LTU
Lithuania	Novartis Investigative Site	Klaipeda	LTU
Lithuania	Novartis Investigative Site	Vilnius
Netherlands	Novartis Investigative Site	Goes
Netherlands	Novartis Investigative Site	Haarlem
Netherlands	Novartis Investigative Site	Heerlen
Netherlands	Novartis Investigative Site	Leiderdorp
Netherlands	Novartis Investigative Site	Roermond
Netherlands	Novartis Investigative Site	Veldhoven
Norway	Novartis Investigative Site	Feiring
Poland	Novartis Investigative Site	Lodz	Lodzkie
Poland	Novartis Investigative Site	Warszawa	Mazowieckie
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Spain	Novartis Investigative Site	Alicante	Comunidad Valenciana
Spain	Novartis Investigative Site	Aranda de Duero	Castilla Y Leon
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Burgos	Castilla Y Leon
Spain	Novartis Investigative Site	Caceres	Extremadura
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	Elche	Alicante
Spain	Novartis Investigative Site	Ferrol	A Coruna
Spain	Novartis Investigative Site	Gijon	Asturias
Spain	Novartis Investigative Site	Girona
Spain	Novartis Investigative Site	Granada	Andalucia
Spain	Novartis Investigative Site	Huelva	Andalucia
Spain	Novartis Investigative Site	Leon	Castilla Y Leon
Spain	Novartis Investigative Site	Lugo	Galicia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Manises	Valencia
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Sabadell	Cataluña
Spain	Novartis Investigative Site	Sanlúcar de Barrameda	Andalucia
Spain	Novartis Investigative Site	Santander	Cantabria
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Soria	Castilla Y Leon
Spain	Novartis Investigative Site	Villamartin	Cadiz
Sweden	Novartis Investigative Site	Lund
Sweden	Novartis Investigative Site	Molndal
Sweden	Novartis Investigative Site	Stockholm
United Kingdom	Novartis Investigative Site	Bournemouth
United Kingdom	Novartis Investigative Site	Cumbria
United Kingdom	Novartis Investigative Site	Faringdon	Oxfordshire
United Kingdom	Novartis Investigative Site	Gateshead	Tyne And Wear
United Kingdom	Novartis Investigative Site	Poole
United Kingdom	Novartis Investigative Site	Rothwell	GBR
United Kingdom	Novartis Investigative Site	Stockton on Tees	Cleveland
United Kingdom	Novartis Investigative Site	Wellingborough

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  Bulgaria,  Czechia,  Denmark,  Estonia,  Finland,  France,  Germany,  Greece,  Iceland,  Ireland,  Latvia,  Lithuania,  Netherlands,  Norway,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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