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

NCT02900378 | Completed Phase 3 Results

• 2 other identifiers: CLCZ696B33012016-003085-32
• Study Type: interventional
• Target: 621
• Locations: 18 countries
• Sites: 116

Brief 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).

Conditions

Chronic Heart Failure With Reduced Ejection Fraction

Keywords

sacubitril/valsartan; enalapril; physical activity; actigraphy; sleep; heart failure; reduced ejection fraction; randomized controlled trial; accelerometry

Outcome Measures

Primary Outcomes (2)

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

  The impact of LCZ696 (Sacubitril/Valsartan) and Enalapril on functional exercise capacity was measured by the Six Minute Walk Test at 12 weeks. The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway.

  Baseline, Week 12

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

  Non-sedentary physical activity is defined as \>= 178.50 activity counts per minute; the average number of minutes per day spent in non-sedentary physical activity is being calculated over 14 days before randomization (baseline i.e. week -2 to week 0) and the last 14 days of treatment (i.e. week 10 to week 12).

  Baseline, Week 12

Secondary Outcomes (18)

• Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS

  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

  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

  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

  Baseline, Week 12

• Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS

  Baseline, Week 12

Study Arms (2)

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.

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

Drug: Placebo of LCZ696 (Sacubitril/Valsartan); Drug: Enalapril

Interventions

LCZ696 (Sacubitril/Valsartan) DRUG

LCZ696 (sacubitril/valsartan) was available in 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets

Also known as: LCZ696

LCZ696 (Sacubitril/Valsartan)

Placebo of LCZ696 (Sacubitril/Valsartan) DRUG

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

Also known as: Placebo

Enalapril

Enalapril DRUG

Enalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets

Enalapril

Placebo of Enalapril DRUG

Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets

Also known as: Placebo

LCZ696 (Sacubitril/Valsartan)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (119)

Novartis Investigative Site

Edegem, Antwerpen, 2650, Belgium

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Dendermonde, 9200, Belgium

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Geel, 2440, Belgium

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Ghent, 9000, Belgium

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Turnhout, 2300, Belgium

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Pleven, 5800, Bulgaria

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Plovdiv, 4000, Bulgaria

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Sofia, 1233, Bulgaria

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Sofia, 1606, Bulgaria

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Sofia, 1709, Bulgaria

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Brno, Czech Republic, 60200, Czechia

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Chomutov, Czech Republic, 43001, Czechia

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Svitavy, Czech Republic, 568 25, Czechia

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Most, CZE, 434 01, Czechia

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Kolín, 280 20, Czechia

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Prague, 106 00, Czechia

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Prague, 150 00, Czechia

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Elsinore, DK-3000, Denmark

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Odense C, DK 5000, Denmark

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Randers, 8930, Denmark

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Roskilde, 4000, Denmark

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Svendborg, 5700, Denmark

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Tallinn, 10138, Estonia

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Tallinn, 13419, Estonia

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Tartu, 51014, Estonia

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Hämeenlinna, 13100, Finland

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Tampere, 33520, Finland

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Auxerre, 89000, France

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Clermont-Ferrand, 63003, France

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Metz-Tessy, 74370, France

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Dresden, Saxony, 01099, Germany

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Bad Homburg, 61348, Germany

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Berlin, 10787, Germany

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Berlin, 10789, Germany

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Berlin, 13055, Germany

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Berlin, 13353, Germany

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Buchholz in der Nordheide, 21244, Germany

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Dietzenbach, 63128, Germany

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Elsterwerda, 04910, Germany

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Essen, 45355, Germany

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Frankfurt, 60594, Germany

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Halberstadt, 38820, Germany

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Hamburg, 22041, Germany

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Haßloch, 67454, Germany

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Leipzig, 04103, Germany

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Löhne, 32584, Germany

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Mannheim, 68165, Germany

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Mühldorf, 84453, Germany

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Nuremberg, 90402, Germany

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Reinfeld, 23858, Germany

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Schwäbisch Hall, 74523, Germany

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Siegen, 57 072, Germany

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Wallerfing, 94574, Germany

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Wedel, 22880, Germany

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Wermsdorf, 04779, Germany

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Alexandroupoli, Evros, 681 00, Greece

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Heraklion Crete, Greece, 711 10, Greece

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Voula, GR, 166 73, Greece

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Athens, 115 27, Greece

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Athens, 151 27, Greece

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Kopavogur, 201, Iceland

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Reykjavik, IS-101, Iceland

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Dublin, Ireland

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Jelgava, 3001, Latvia

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Ogre, 5001, Latvia

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Riga, 1012, Latvia

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Riga, LV 1002, Latvia

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Riga, LV-1001, Latvia

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Kaunas, LTU, LT 50161, Lithuania

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Klaipėda, LTU, LT-92288, Lithuania

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Vilnius, LT-08661, Lithuania

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Goes, 4462 RA, Netherlands

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Haarlem, 2035 RC, Netherlands

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Heerlen, 6419, Netherlands

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Leiderdorp, 2353 GA, Netherlands

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Roermond, 6043 CV, Netherlands

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Veldhoven, 5504 DB, Netherlands

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Feiring, 2093, Norway

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Warsaw, Masovian Voivodeship, 02-676, Poland

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Warsaw, 02-097, Poland

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Warsaw, 02-507, Poland

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Warsaw, 05077, Poland

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Lodz, Łódź Voivodeship, 91425, Poland

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Ferrol, A Coruna, 15405, Spain

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Elche, Alicante, 03293, Spain

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Córdoba, Andalusia, 14004, Spain

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Granada, Andalusia, 18014, Spain

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Huelva, Andalusia, 21005, Spain

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Sanlúcar de Barrameda, Andalusia, 11540, Spain

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Seville, Andalusia, 41009, Spain

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Villamartín, Cadiz, 11650, Spain

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Santander, Cantabria, 39008, Spain

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Aranda de Duero, Castille and León, 09400, Spain

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Burgos, Castille and León, 09006, Spain

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León, Castille and León, 24071, Spain

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Soria, Castille and León, 42005, Spain

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Sabadell, Catalonia, 08208, Spain

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Cáceres, Extremadura, 10003, Spain

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Lugo, Galicia, 27003, Spain

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Santiago de Compostela, Galicia, 15706, Spain

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Gijón, Principality of Asturias, 33290, Spain

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Oviedo, Principality of Asturias, 33011, Spain

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Alicante, Valencia, 03010, Spain

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Manises, Valencia, 46940, Spain

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Barcelona, 08041, Spain

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Girona, 17007, Spain

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Madrid, 28031, Spain

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Madrid, 28222, Spain

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Lund, 222 21, Sweden

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Mölndal, 431 80, Sweden

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Stockholm, 17176, Sweden

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Stockton-on-Tees, Cleveland, TS19 8PE, United Kingdom

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Rothwell, GBR, NN14 6JQ, United Kingdom

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Faringdon, Oxfordshire, SN7 7YU, United Kingdom

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Gateshead, Tyne and Wear, NE9 6SX, United Kingdom

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Bournemouth, BH7 7DW, United Kingdom

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Cumbria, CA139HT, United Kingdom

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Poole, BH15 2JB, United Kingdom

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Wellingborough, NN8 4RW, United Kingdom

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MeSH Terms

Conditions

Motor Activity; Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; sacubitril; Valsartan; Enalapril

Condition Hierarchy (Ancestors)

Behavior; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Dipeptides; Oligopeptides; Peptides

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2016
• First Posted: September 14, 2016
• Study Start: December 20, 2016
• Primary Completion: April 11, 2018
• Study Completion: April 11, 2018
• Last Updated: September 2, 2020
• Results First Posted: September 16, 2019

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will share

Locations

BE (5); SE (3); CZ (7); PL (5); NL (6); DE (25); IC (2); DK (5); NO (1); FI (2); ES (25); LI (3); IE (1); FR (3); GR (5); LA (5); GB (8); BU (5)