Chronic Heart Failure With Reduced Ejection FractionPhase 3OUTSTEP-HFNCT02900378

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

A Phase 3 study testing LCZ696 (Sacubitril/Valsartan) and Enalapril in people with Chronic Heart Failure With Reduced Ejection Fraction, run by Novartis Pharmaceuticals at 119 sites in 19 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial summary

Who is it for?: Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for: Chronic Heart Failure With Reduced Ejection Fraction
What is being tested?: LCZ696 (Sacubitril/Valsartan) and Enalapril
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 621 participants
Where: 119 sitesin 19 countries
Study dates: 20 Dec 2016to 11 Apr 2018
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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.

Who cannot join

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.

Trial locations and contacts

119 sites in 19 countries.

Country

City, postcode or hospital

119 sites in 19 countries

Germany25 sites

Novartis Investigative Site
Bad Homburg, 61348
Novartis Investigative Site
Berlin, 10787
Novartis Investigative Site
Berlin, 10789
Novartis Investigative Site
Berlin, 13055
Novartis Investigative Site
Berlin, 13353
Novartis Investigative Site
Buchholz in der Nordheide, 21244
Novartis Investigative Site
Dietzenbach, 63128
Novartis Investigative Site
Dresden, Saxony, 01099
Novartis Investigative Site
Elsterwerda, 04910
Novartis Investigative Site
Essen, 45355
Novartis Investigative Site
Frankfurt, 60594
Novartis Investigative Site
Halberstadt, 38820
Novartis Investigative Site
Hamburg, 22041
Novartis Investigative Site
Haßloch, 67454
Novartis Investigative Site
Leipzig, 04103
Novartis Investigative Site
Löhne, 32584
Novartis Investigative Site
Mannheim, 68165
Novartis Investigative Site
Mühldorf, 84453
Novartis Investigative Site
Nuremberg, 90402
Novartis Investigative Site
Reinfeld, 23858
Novartis Investigative Site
Schwäbisch Hall, 74523
Novartis Investigative Site
Siegen, 57 072
Novartis Investigative Site
Wallerfing, 94574
Novartis Investigative Site
Wedel, 22880
Novartis Investigative Site
Wermsdorf, 04779

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Spain25 sites

Novartis Investigative Site
Alicante, Valencia, 03010
Novartis Investigative Site
Aranda de Duero, Castille and León, 09400
Novartis Investigative Site
Barcelona, 08041
Novartis Investigative Site
Burgos, Castille and León, 09006
Novartis Investigative Site
Cáceres, Extremadura, 10003
Novartis Investigative Site
Córdoba, Andalusia, 14004
Novartis Investigative Site
Elche, Alicante, 03293
Novartis Investigative Site
Ferrol, A Coruna, 15405
Novartis Investigative Site
Gijón, Principality of Asturias, 33290
Novartis Investigative Site
Girona, 17007
Novartis Investigative Site
Granada, Andalusia, 18014
Novartis Investigative Site
Huelva, Andalusia, 21005
Novartis Investigative Site
León, Castille and León, 24071
Novartis Investigative Site
Lugo, Galicia, 27003
Novartis Investigative Site
Madrid, 28031
Novartis Investigative Site
Madrid, 28222
Novartis Investigative Site
Manises, Valencia, 46940
Novartis Investigative Site
Oviedo, Principality of Asturias, 33011
Novartis Investigative Site
Sabadell, Catalonia, 08208
Novartis Investigative Site
Sanlúcar de Barrameda, Andalusia, 11540
Novartis Investigative Site
Santander, Cantabria, 39008
Novartis Investigative Site
Santiago de Compostela, Galicia, 15706
Novartis Investigative Site
Seville, Andalusia, 41009
Novartis Investigative Site
Soria, Castille and León, 42005
Novartis Investigative Site
Villamartín, Cadiz, 11650

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United Kingdom8 sites

Novartis Investigative Site
Bournemouth, BH7 7DW
Novartis Investigative Site
Cumbria, CA139HT
Novartis Investigative Site
Faringdon, Oxfordshire, SN7 7YU
Novartis Investigative Site
Gateshead, Tyne and Wear, NE9 6SX
Novartis Investigative Site
Poole, BH15 2JB
Novartis Investigative Site
Rothwell, GBR, NN14 6JQ
Novartis Investigative Site
Stockton-on-Tees, Cleveland, TS19 8PE
Novartis Investigative Site
Wellingborough, NN8 4RW

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Czechia7 sites

Novartis Investigative Site
Brno, Czech Republic, 60200
Novartis Investigative Site
Chomutov, Czech Republic, 43001
Novartis Investigative Site
Kolín, 280 20
Novartis Investigative Site
Most, CZE, 434 01
Novartis Investigative Site
Prague, 106 00
Novartis Investigative Site
Prague, 150 00
Novartis Investigative Site
Svitavy, Czech Republic, 568 25

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Netherlands6 sites

Novartis Investigative Site
Goes, 4462 RA
Novartis Investigative Site
Haarlem, 2035 RC
Novartis Investigative Site
Heerlen, 6419
Novartis Investigative Site
Leiderdorp, 2353 GA
Novartis Investigative Site
Roermond, 6043 CV
Novartis Investigative Site
Veldhoven, 5504 DB

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Belgium5 sites

Novartis Investigative Site
Dendermonde, 9200
Novartis Investigative Site
Edegem, Antwerpen, 2650
Novartis Investigative Site
Geel, 2440
Novartis Investigative Site
Ghent, 9000
Novartis Investigative Site
Turnhout, 2300

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Bulgaria5 sites

Novartis Investigative Site
Pleven, 5800
Novartis Investigative Site
Plovdiv, 4000
Novartis Investigative Site
Sofia, 1233
Novartis Investigative Site
Sofia, 1606
Novartis Investigative Site
Sofia, 1709

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Denmark5 sites

Novartis Investigative Site
Elsinore, DK-3000
Novartis Investigative Site
Odense C, DK 5000
Novartis Investigative Site
Randers, 8930
Novartis Investigative Site
Roskilde, 4000
Novartis Investigative Site
Svendborg, 5700

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Greece5 sites

Novartis Investigative Site
Alexandroupoli, Evros, 681 00
Novartis Investigative Site
Athens, 115 27
Novartis Investigative Site
Athens, 151 27
Novartis Investigative Site
Heraklion Crete, Greece, 711 10
Novartis Investigative Site
Voula, GR, 166 73

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Latvia5 sites

Novartis Investigative Site
Jelgava, 3001
Novartis Investigative Site
Ogre, 5001
Novartis Investigative Site
Riga, 1012
Novartis Investigative Site
Riga, LV 1002
Novartis Investigative Site
Riga, LV-1001

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Poland5 sites

Novartis Investigative Site
Lodz, Łódź Voivodeship, 91425
Novartis Investigative Site
Warsaw, Masovian Voivodeship, 02-676
Novartis Investigative Site
Warsaw, 02-097
Novartis Investigative Site
Warsaw, 02-507
Novartis Investigative Site
Warsaw, 05077

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Estonia3 sites

Novartis Investigative Site
Tallinn, 10138
Novartis Investigative Site
Tallinn, 13419
Novartis Investigative Site
Tartu, 51014

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France3 sites

Novartis Investigative Site
Auxerre, 89000
Novartis Investigative Site
Clermont-Ferrand, 63003
Novartis Investigative Site
Metz-Tessy, 74370

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Lithuania3 sites

Novartis Investigative Site
Kaunas, LTU, LT 50161
Novartis Investigative Site
Klaipėda, LTU, LT-92288
Novartis Investigative Site
Vilnius, LT-08661

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Sweden3 sites

Novartis Investigative Site
Lund, 222 21
Novartis Investigative Site
Mölndal, 431 80
Novartis Investigative Site
Stockholm, 17176

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Finland2 sites

Novartis Investigative Site
Hämeenlinna, 13100
Novartis Investigative Site
Tampere, 33520

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Iceland2 sites

Novartis Investigative Site
Kopavogur, 201
Novartis Investigative Site
Reykjavik, IS-101

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Ireland1 site

Novartis Investigative Site
Dublin

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Norway1 site

Novartis Investigative Site
Feiring, 2093

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About this study

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

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).

Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Being tested: LCZ696 (Sacubitril/Valsartan), Placebo of LCZ696 (Sacubitril/Valsartan), Enalapril, Placebo of Enalapril
Keywords: sacubitril/valsartan, enalapril, physical activity, actigraphy, sleep, heart failure, reduced ejection fraction, randomized controlled trial, accelerometry
Medical subject headings: Motor Activity, Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

LCZ696 (Sacubitril/Valsartan)Drug
Also called LCZ696
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)Drug
Also called Placebo
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
EnalaprilDrug
Enalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets
Placebo of EnalaprilDrug
Also called Placebo
Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets

Study groups in NCT02900378
Study group	Role	What they receive
LCZ696 (Sacubitril/Valsartan)	Experimental	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. Receives: Drug: LCZ696 (Sacubitril/Valsartan); Drug: Placebo of Enalapril
Enalapril	Active comparator	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 Receives: Drug: Placebo of LCZ696 (Sacubitril/Valsartan); Drug: Enalapril

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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).
Measured: Baseline, Week 12

Secondary outcomes (18)

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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)
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, Week 2, Week 4, Week 6, Week 8 and Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

20 Dec 201611 Apr 2018

First posted14 Sep 2016 (estimated)
Study start20 Dec 2016
Primary completion11 Apr 2018
Study completion11 Apr 2018

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Chronic Heart Failure With Reduced Ejection FractionStudies of the same condition, open and under way.
More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Investigator, Outcomes assessor
Enrolment: 621 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02900378
Sponsor's protocol ID: CLCZ696B3301
Other IDs: 2016-003085-32, 2016
Acronym: OUTSTEP-HF
Status last verified: Sep 2020
First submitted: 9 Sep 2016
Last updated: 2 Sep 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Chronic Heart Failure With Reduced Ejection Fraction trials

Study at a glance

From the registry record, last updated by the sponsor on 2 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT02900378
Acronym / sponsor ID: OUTSTEP-HF / CLCZ696B3301
Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Keywords: sacubitril/valsartan, enalapril, physical activity, actigraphy, sleep, heart failure, reduced ejection fraction, randomized controlled trial
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 621 participants (actual)
Lead sponsor: Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: 20 Dec 2016 (actual)
Primary completion: 11 Apr 2018 (actual)
Study completion: 11 Apr 2018 (actual)
First posted: 14 Sep 2016 (estimated)
Results: Posted 16 Sep 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
LCZ696 (Sacubitril/Valsartan)	Experimental	Drug: LCZ696 (Sacubitril/Valsartan), Drug: Placebo of EnalaprilAfter 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.
Enalapril	Active comparator	Drug: Placebo of LCZ696 (Sacubitril/Valsartan), Drug: EnalaprilAfter 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

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (8 listed)

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%
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

Key exclusion criteria (6 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
LCZ696 (Sacubitril/Valsartan)Also: LCZ696LCZ696 (sacubitril/valsartan) was available in 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets	Drug	LCZ696 (Sacubitril/Valsartan)
Placebo of LCZ696 (Sacubitril/Valsartan)Also: PlaceboPlacebo of LCZ696 (sacubitril/valsartan) was available to match 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets	Drug	Enalapril
EnalaprilEnalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets	Drug	Enalapril
Placebo of EnalaprilAlso: PlaceboPlacebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets	Drug	LCZ696 (Sacubitril/Valsartan)

Primary outcome

Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12)
Time frame: Baseline, 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.
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12)
Time frame: Baseline, 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).

18 secondary outcomes

Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, Week 12
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS
Time frame: 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
Time frame: Baseline, Week 12
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8
Time frame: 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
Time frame: Baseline, Week 12
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12
Time frame: Week 4, Week 8, Week 12
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA)
Time frame: Week 4, Week 8, Week 12
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8 and Week 12

Results and safety

Results posted to the registry on 16 Sep 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
LCZ696 (Sacubitril/Valsartan)	310	287
Enalapril	311	283

Primary outcome: Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12)

Time frame: Baseline, Week 12. Mean (Standard Deviation). Unit: meters

Measure	LCZ696 (Sacubitril/Valsartan) n = 302	Enalapril n = 302
Baseline (FAS)	365.37 (108.18)	371.08 (104.41)
Week 12 (FAS)	395.80 (113.11)	395.33 (105.94)
Change from BL at Week 12 (FAS)	31.57 (67.35)	24.89 (51.64)
Baseline (FAS without AE/SAE)	364.72 (106.86)	371.18 (105.13)
Week 12 (FAS without AE/SAE)	399.31 (110.54)	396.02 (106.39)
Change from BL at Week 12 (FAS without AE/SAE)	35.75 (58.76)	25.87 (51.73)

LCZ696 (Sacubitril/Valsartan) vs Enalapril: Differences of least square means: 5.68 (95% CI -3.93 to 15.29), p = 0.2464, ANCOVA
LCZ696 (Sacubitril/Valsartan) vs Enalapril: Differences of least square means: 8.98 (97.5% CI -1.31 to 19.27), p = 0.0503, ANCOVA

Population analysed: The Full Analysis Set (FAS) and FAS population subset without AE/SAE were considered

Primary outcome: Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12)

Time frame: Baseline, Week 12. Mean (Standard Deviation). Unit: minutes

Measure	LCZ696 (Sacubitril/Valsartan) n = 302	Enalapril n = 302
Baseline (FAS with MI)	510.11 (128.08)	506.81 (139.60)
Week 12 (FAS with MI)	479.69 (124.23)	487.53 (126.84)
Change from BL at Week 12 (FAS with MI)	-30.42 (102.55)	-19.28 (104.04)
Baseline (FAS with LOCF)	512.07 (126.37)	505.31 (129.74)
Week 12 (FAS with LOCF)	489.43 (127.36)	490.09 (127.82)
Change from BL at Week 12 (FAS with LOCF)	-21.88 (68.55)	-15.41 (74.45)
Baseline (FAS without MI/LOCF)	512.07 (126.37)	505.31 (129.74)
Week 12 (FAS without MI/LOCF)	479.81 (122.45)	486.85 (128.70)

LCZ696 (Sacubitril/Valsartan) vs Enalapril: Differences of least square means: -6.14 (97.5% CI -25.70 to 13.41), p = 0.4769, ANCOVA
LCZ696 (Sacubitril/Valsartan) vs Enalapril: Differences of least square means: -5.67 (95% CI -17.48 to 6.14), p = 0.3463, ANCOVA
LCZ696 (Sacubitril/Valsartan) vs Enalapril: Differences of least square means: -6.24 (95% CI -19.39 to 6.91), p = 0.3513, ANCOVA

Population analysed: The FAS population with Multiple Imputation (MI), with Last Observation Carried Forward (LOCF) and without MI/LOCF were considered.

18 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
LCZ696 (Sacubitril/Valsartan)	19 of 309 (6.1%)	168 of 309 (54.4%)	1 of 309
Enalapril	28 of 310 (9%)	143 of 310 (46.1%)	4 of 310

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 2 Sep 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Novartis Pharmaceuticals study director

Novartis Pharmaceuticals

119 sites in 19 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing LCZ696 (Sacubitril/Valsartan) and Enalapril in people with Chronic Heart Failure With Reduced Ejection Fraction, run by Novartis Pharmaceuticals at 119 sites in 19 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 119 sites in Germany, Spain, United Kingdom, Czechia, Netherlands and 14 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) (time frame: Baseline, Week 12). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02900378.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Sep 2020.