The Effects of Sacubitril/Valsartan on Cardiac Oxygen Consumption and Efficiency of Cardiac Work in Heart Failure Patients

NCT03300427 | Completed Phase 4 Results

• 2 other identifiers: CLCZ696BFI032017-002113-64
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase IV, prospective, randomized, double-blind, double-dummy, parallel-group study. The study assessed the effects of 6 weeks of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on the efficiency of cardiac work in patients with NYHA II-III heart failure (HF) and reduced systolic function using 11C-acetate positron emission tomography (PET) and echocardiography.

Conditions

Heart Failure

Keywords

Heart failure with reduced left ventricular ejection fraction; LVEF; Cardiac dysfunction; Heart muscle dysfunction; Left ventricular (LV) dilation; Left ventricular hypertrophy; HF; AHF; CHF; CCF; acute heart failure; chronic heart failure; congestive heart failure; congestive cardiac failure

Outcome Measures

Primary Outcomes (4)

• Myocardial Energetic Efficiency

  Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan. Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono Where * SBP : Systolic blood pressure during PET * SV : Stroke volume (Echocardiography) * HR : Heart rate * Kmono: Mono-exponential clearance rate (11C-acetate PET- scan) * LV mass: Left ventricular mass Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed. No imputation of missing data was performed.

  Baseline, Visit 3 (approximately Week 8)

• Change From Baseline in Myocardial Energetic Efficiency

  Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan. Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono Where * SBP : Systolic blood pressure during PET * SV : Stroke volume (Echocardiography) * HR : Heart rate * Kmono: Mono-exponential clearance rate (11C-acetate PET- scan) * LV mass: Left ventricular mass Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed. No imputation of missing data was performed.

  Baseline, Visit 3 (approximately Week 8)

• Viable Myocardial Energetic Efficiency (Sensitivity Analysis)

  In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as: Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy.

  Baseline, Visit 3 (approximately Week 8)

• Change From Baseline in Viable Myocardial Energetic Efficiency (Sensitivity Analysis)

  In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as: Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy.

  Baseline, Visit 3 (approximately Week 8)

Study Arms (2)

sacubitril/valsartan

EXPERIMENTAL

subjects received sacubitril/valsartan 100 mg orally twice daily (BID). The dose was then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration was not possible).

Drug: sacubitril/valsatran; Drug: placebo to valsartan

valsartan

ACTIVE COMPARATOR

subjects received 80 mg orally twice daily (BID). The dose was then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration was not possible)

Drug: valsartan; Drug: placebo to sacubitril/valsartan

Interventions

sacubitril/valsatran DRUG

sacubitril/valsatran 100 or 200 mg BID

sacubitril/valsartan

valsartan DRUG

Valsartan 80 or 160 mg BID

valsartan

placebo to valsartan DRUG

placebo to valsartan 80 or 160 BID

sacubitril/valsartan

placebo to sacubitril/valsartan DRUG

placebo to sacubitril/valsartan 100 or 200 mg BID

valsartan

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age
• Chronic HF with reduced EF (left ventricle EF 25-35%) and NYHA class II-III symptoms.
• Systolic BP 110-160 mm Hg
• Optimal standard HF therapy according to European Society of Cardiology (ESC) guidelines at a stable dose for at least 4 weeks before the screening visit.

You may not qualify if:

• Estimated glomerular filtration rate (eGFR) \< 45 ml/min
• Serum potassium \> 5.2 mmol/l and creatinine \>1.5 x ULN

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (1)

Novartis Investigative Site

Turku, 20521, Finland

Location

MeSH Terms

Conditions

Heart Failure; Dilatation, Pathologic; Hypertrophy, Left Ventricular

Interventions

sacubitril; Valsartan

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Cardiomegaly; Hypertrophy

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2017
• First Posted: October 3, 2017
• Study Start: July 5, 2018
• Primary Completion: March 23, 2022
• Study Completion: March 23, 2022
• Last Updated: January 5, 2024
• Results First Posted: January 5, 2024

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share

Locations

FI (1)