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randOmized stUdy Using acceleromeTry to Compare Sacubitril/valsarTan and Enalapril in Patients With Heart Failure (OUTSTEP-HF)

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ClinicalTrials.gov Identifier: NCT02900378
Recruitment Status : Completed
First Posted : September 14, 2016
Results First Posted : September 16, 2019
Last Update Posted : September 2, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE September 9, 2016
First Posted Date  ICMJE September 14, 2016
Results First Submitted Date  ICMJE April 11, 2019
Results First Posted Date  ICMJE September 16, 2019
Last Update Posted Date September 2, 2020
Actual Study Start Date  ICMJE December 20, 2016
Actual Primary Completion Date April 11, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 8, 2019)
  • 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).
Original Primary Outcome Measures  ICMJE
 (submitted: September 9, 2016)
Change from baseline in mean daily non-sedentary daytime activity between baseline and end of study [ Time Frame: Baseline (week -2 to Week 0), last 14 days of treatment (week 10 to 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 will be 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).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 8, 2019)
  • Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS [ Time Frame: Baseline, Week 12 ]
    The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group.
  • 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 ]
    The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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)
  • Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 [ Time Frame: Week 4, Week 8, Week 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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2016)
  • Percentage of patients with improved symptoms of heart failure as assessed by Patient Global Assessment [ Time Frame: Week 4, Week 8, Week 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.
  • Change from baseline in mean daily non-sedentary daytime activity in weekly and two-weekly intervals [ Time Frame: Week - 1 to Week 0, Week - 2 to Week 0, from week 0 to Week 12 ]
    Non-sedentary physical activity is defined as ≥178.50 activity counts per minute; Mean daily non-sedentary daytime physical activity will be calculated over weekly and two-weekly intervals and compared to before the inclusion (week - 1 to week 0/week - 2 to week 0 respectively).
  • Change from baseline in mean daily non-sedentary daytime physical activity classified by its intensity [ Time Frame: Baseline (week - 2 to week 0), week 2 to week 4, week 6 to week 8, week 10 to week 12 ]
    The average number of minutes per day spent in the different non-sedentary physical activity categories (light and moderateto- vigorous) will be calculated over 14 day epochs. Non-sedentary physical activity is defined as ≥178.5 activity counts per minute; light physical activity is defined as 178.5 - 565.5 counts per minute; moderate-to vigorous activity is defined as > 565.5 counts per minute.
  • Total Weekly Time Spent in Non-sedentary Daytime Physical Activity [ Time Frame: week 0 to week 12 in weekly intervals ]
    Non-sedentary physical activity is defined as ≥178.5 activity counts per minute; The total time spent in non-sedentary physical activity will be calculated for each patient in weekly intervals and the temporal course for each patient will be assessed.
  • Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity [ Time Frame: week 0 to week 12 in weekly intervals ]
    Light non-sedentary daytime physical activity is defined as 178.5 - 565.5 counts per minute; The time spent in light non-sedentary physical activity will be calculated for each patient in weekly intervals and the temporal course for each patient will be assessed.
  • Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity [ Time Frame: week 0 to week 12 in weekly intervals ]
    Moderate-to-vigorous non-sedentary physical activity is defined as 178.5 to 565.5 counts per minute. The total time spent in moderate-to-vigorous non-sedentary physical activity will be calculated for each patient in weekly intervals and the temporal course for each patient will be assessed.
  • Change From Baseline in Peak Six Minutes of Daytime Physical Activity [ Time Frame: week -2 to week 0, week 2 to week 4, week 6 to week 8, week 10 to week 12 ]
    The peak 6 min walk (M6min) is a parameter derived by validated algorithms of the software that will be used to preprocess actigraphy data. The parameter reflects the peak 6 minutes of day time physical activity. The mean daily 6-minute walking test will be calculated over 14 day intervals.
  • Change from baseline in means of 6-minute walking test [ Time Frame: week 0, week 4, week 8, week 12 ]
    The analysis will report change from baseline in exercise capacity which will be assessed by means of the 6-minute walking test at weeks 4, 8 and 12
  • Percentage of patients who show increased levels of non-sedentary daytime [ Time Frame: Baseline (week -2 to week 0), Week 12 ]
    Non-sedentary physical activity is defined as ≥178.50 activity counts per minute. Increased levels is defined as ≥ 10% increase of non-sedentary physical activity at week 12 compared to baseline.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE randOmized stUdy Using acceleromeTry to Compare Sacubitril/valsarTan and Enalapril in Patients With Heart Failure
Official Title  ICMJE 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
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Chronic Heart Failure With Reduced Ejection Fraction
Intervention  ICMJE
  • 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
    Other Name: LCZ696
  • Drug: 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
    Other Name: Placebo
  • Drug: Enalapril
    Enalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets
  • Drug: Placebo of Enalapril
    Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets
    Other Name: Placebo
Study Arms  ICMJE
  • Experimental: LCZ696 (Sacubitril/Valsartan)
    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.
    Interventions:
    • Drug: LCZ696 (Sacubitril/Valsartan)
    • Drug: Placebo of Enalapril
  • Active Comparator: Enalapril
    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
    Interventions:
    • Drug: Placebo of LCZ696 (Sacubitril/Valsartan)
    • Drug: Enalapril
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 4, 2019)
621
Original Estimated Enrollment  ICMJE
 (submitted: September 9, 2016)
600
Actual Study Completion Date  ICMJE April 11, 2018
Actual Primary Completion Date April 11, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Bulgaria,   Czechia,   Denmark,   Estonia,   Finland,   France,   Germany,   Greece,   Iceland,   Ireland,   Latvia,   Lithuania,   Netherlands,   Norway,   Poland,   Spain,   Sweden,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02900378
Other Study ID Numbers  ICMJE CLCZ696B3301
2016-003085-32 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

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

URL: https://www.clinicalstudydatarequest.com
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP