Exercise Capacity Study of LCZ696 vs. Enalapril in Patients With Chronic Heart Failure and Reduced Ejection Fraction.

A Randomized, Double-blind, Active-controlled Study to Assess the Effect of LCZ696 Compared With Enalapril to Improve Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF).

The purpose of the study was to determine the effect of LCZ696 vs. enalapril on improvement of exercise capacity in patients with chronic heart failure with reduced ejection fraction.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: LCZ696; Drug: Placebo matching enalapril; Drug: Enalapril; Drug: Placebo matching LCZ696

Detailed Description

This study was a randomized, double-blind, double-dummy, parallel-group, active-controlled, two-arm trial to compare LCZ696 200 mg twice daily (bid) to enalapril 10 mg bid in improving exercise capacity, daily physical activity and quality of life in patients with stable chronic heart failure (New York Heart Association III) and reduced left ventricular ejection fraction (LVEF ≤ 40%).

The study consisted of a screening period of 2 weeks during which the subject's eligibility for the study was assessed followed by a double blind treatment period of 12 weeks. Eligible subjects were randomized 1:1 to receive either LCZ696 or enalapril during the double-blind period. Treatment was initiated with LCZ696 100 mg bid or enalapril 5 mg bid (enalapril 10 mg bid for patients at a stable daily dose of enalapril above 10 mg per day or corresponding doses of other angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) prior first screening visit), respectively. Dose was up-titrated after 2 weeks to the final dose of LCZ696 200 mg bid or enalapril 10 mg bid.

Patients continued to take their background medications for chronic heart failure during the study, with the exception of ACEI or ARBs which were replaced by investigational treatment and had to be discontinued before first dose of study drug.

The primary objective was to demonstrate the superiority of LCZ696 200 mg bid compared to enalapril 10 mg bid in improving exercise tolerance (peak respiratory oxygen uptake (VO2peak), adjusted to body weight) as assessed by cardio-pulmonary-exercise testing (CPET) in patients with stable chronic heart failure (NYHA III) and reduced ejection fraction (LVEF ≤ 40%) after 3 months treatment.

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Berlin, Germany, 10787
    • Novartis Investigative Site
  • Berlin, Germany, 13405
    • Novartis Investigative Site
  • Berlin, Germany, 13055
    • Novartis Investigative Site
  • Bonn, Germany, 53115
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Dresden, Germany, 01277
    • Novartis Investigative Site
  • Erfurt, Germany, 99089
    • Novartis Investigative Site
  • Frankfurt, Germany, 60389
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Gottingen, Germany, 37075
    • Novartis Investigative Site
  • Hamburg, Germany, 22291
    • Novartis Investigative Site
  • Heidelberg, Germany, 69115
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Koblenz, Germany, 56068
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
  • Koeln, Germany, 51065
    • Novartis Investigative Site
  • Koeln-Nippes, Germany, 50733
    • Novartis Investigative Site
  • Leverkusen, Germany, 51375
    • Novartis Investigative Site
  • Ludwigsburg, Germany, 71634
    • Novartis Investigative Site
  • Ludwigshafen, Germany, 67063
    • Novartis Investigative Site
  • Muenchen, Germany, 81675
    • Novartis Investigative Site
  • Neuwied, Germany, 56564
    • Novartis Investigative Site
  • Nienburg, Germany, 31582
    • Novartis Investigative Site
  • Rotenburg an der Fulda, Germany, 36199
    • Novartis Investigative Site
  • Rüdersdorf, Germany, 15562
    • Novartis Investigative Site
  • Siegen, Germany, 57072
    • Novartis Investigative Site
  • Ulm, Germany, 89077
    • Novartis Investigative Site
  • Villingen-Schwenningen, Germany, 78052
    • Novartis Investigative Site
  • Worms, Germany, 67550
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
  • Wuppertal, Germany, 42117
    • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01099
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with a diagnosis of chronic heart failure (NYHA class III) and reduced ejection fraction (LVEF ≤ 40%)
• Reduced ability to exercise, evidenced by VO2peak ≤ 18 ml/min per kg
• Patients had to be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks prior to the screening visit and until randomization visit.

Exclusion Criteria:

• History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs
• Previous history of intolerance to recommended target doses of ACEIs or ARBs
• Known history of angioedema
• Requirement of treatment with both ACEIs and ARBs
• Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)
• Symptomatic hypotension
• Impaired renal function
• Pregnant or nursing (lactating) women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: LCZ696; LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	Drug: LCZ696; LCZ696 100 mg bid for 2 weeks followed by LCZ696 200 mg bid for 10 weeks. Treatment was administered as oral tablets.; Drug: Placebo matching enalapril; Patients randomized to LCZ696 arm also received placebo matching enalapril (enalapril 0 mg tablets) to ensure the blinding during the entire course of the study.
ACTIVE_COMPARATOR: Enalapril; Enalapril 5 mg oral twice daily (bid) for 2 weeks followed by enalapril 10 mg oral bid for 10 weeks. Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.	Drug: Enalapril; Enalapril 5 mg bid for 2 weeks followed by enalapril 10 mg bid for 10 weeks. Treatment was administered as oral tablets. Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.; Drug: Placebo matching LCZ696; Patients randomized to enalapril arm also received placebo matching LCZ696 (LCZ696 0 mg tablets) to ensure the blinding during the entire course of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 3 Months of Treatment	Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the peak respiratory oxygen uptake (VO2peak). CPET to assess VO2peak was performed at a cycle ergometer at baseline (Visit 2, 9 days prior randomization) and after 6 weeks and 3 months of treatment (Visit 6 and Visit 7, respectively). The VO2peak adjusted to body weight was calculated based on the corresponding visit's VO2peak (unadjusted) and body weight data by using the following formula: VO2peak (unadjusted)/body weight. Higher values of VO2peak indicate less symptom severity and therefore a positive change from baseline indicates improvement.	Baseline, 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 6 Weeks of Treatment	Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the peak respiratory oxygen uptake (VO2peak). CPET to assess VO2peak was performed at a cycle ergometer at baseline (Visit 2, 9 days prior randomization) and after 6 weeks and 3 months of treatment (Visit 6 and Visit 7, respectively). The VO2peak adjusted to body weight was calculated based on the corresponding visit's VO2peak (unadjusted) and body weight data by using the following formula: VO2peak (unadjusted)/body weight. A positive change from baseline indicates less symptom severity.	Baseline, 6 weeks
Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope)	Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the minute ventilation (VE) to carbon dioxide output slope (VE/VCO2 slope). High values of VE/VCO2 slope resembles the inability to eliminate CO2 by respiration (inefficient ventilation). A negative change from baseline indicates less symptom severity.	Baseline, 6 weeks, 3 months
Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT)	Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. CPET was performed at a cycle ergometer with a workload that started at 10 watts (W) and then increased by 10W for each 1-minute stage. Exercise capacity assessed as workload in watts was determined at the ventilatory anaerobic threshold (VAT) which represents the transition from aerobic to partially anaerobic glucose metabolism in muscle, leading to increasing carbon dioxide exhalation in comparison to oxygen uptake. A positive change from baseline in exercise capacity (watt) indicates improvement.	Baseline, 6 weeks, 3 months
Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale	The individually perceived exertion, in terms of perceived dyspnea and perceived fatigue, during cardiopulmonary exercise testing (CPET) was assessed by Borg scale which is a 15 point scale, starting from 6 which indicates "No exertion at all" to 20 which means "Maximal exertion". Change in Borg scale for both perceived dyspnea and perceived fatigue were measured at different time points at Baseline (Visit 2, 9 days prior randomization) and 3 months of treatment (Visit 7). Maximum value among the time points at every visit was used for the analysis. A negative change from baseline in Borg value of perceived dyspnea and perceived fatigue indicates improvement.	Baseline, 3 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 12, 2016
• Primary Completion (ACTUAL): November 25, 2019
• Study Completion (ACTUAL): November 25, 2019

Study Registration Dates

• First Submitted: May 9, 2016
• First Submitted That Met QC Criteria: May 9, 2016
• First Posted (ESTIMATE): May 11, 2016

Study Record Updates

• Last Update Posted (ACTUAL): October 8, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: exercise capacity; heart failure; VO2peak; LCZ696; sacubitril/valsartan; systolic heart failure; heart failure with reduced ejection fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Enalapril; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696BDE01; 2015-004632-35 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No