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

Controlled Trial on the Short-term Effects of Sacubitril/Valsartan Therapy on Cardiac Oxygen Consumption and Efficiency of Cardiac Work in Patients With NYHA II-III Heart Failure and Reduced Systolic Function Using 11C-acetate Positron Emission Tomography and Echocardiography

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: sacubitril/valsatran; Drug: placebo to valsartan; Drug: valsartan; Drug: placebo to sacubitril/valsartan

Detailed Description

Subjects were randomized into valsartan or sacubitril/valsartan arms in a 1:1 ratio. Regardless of the treatment arm a subject is in, the study drug was up-titrated to the highest tolerated dose level during the scheduled study visits. The different strengths of the two study drugs were not identical in appearance so the possible dose modification(s) during the treatment period could not be performed in a blinded manner. Subjects started on valsartan 80 mg BID or sacubitril/valsartan 100 mg BID dose and there was only one scheduled up-titration visit after the randomization. Exception for this were the subjects that were on valsartan 160 mg BID dose during the run-in phase. These subjects were randomized directly to valsartan 160 mg BID or sacubitril/valsartan 100 mg BID. Subjects that were randomized to valsartan arm had similar visit after which they continued on the same dose. For subjects that were randomized from valsartan 160 mg BID to sacubitril/valsartan 100 mg BID the dose was up-titrated to 200 mg BID if clinically possible.

The total duration for each patient was planned to be about 14 weeks but could be longer if required for scheduling purposes . The longest participation, from signing of ICF until end of study, was 26 weeks.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 4

Contacts and Locations

Study Locations

• Finland
  • Turku, Finland, 20521
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• 40-80 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.

Exclusion criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sacubitril/valsartan; 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; sacubitril/valsatran 100 or 200 mg BID; Drug: placebo to valsartan; placebo to valsartan 80 or 160 BID
Active Comparator: valsartan; 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; Valsartan 80 or 160 mg BID; Drug: placebo to sacubitril/valsartan; placebo to sacubitril/valsartan 100 or 200 mg BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2018
• Primary Completion (Actual): March 23, 2022
• Study Completion (Actual): March 23, 2022

Study Registration Dates

• First Submitted: September 28, 2017
• First Submitted That Met QC Criteria: September 28, 2017
• First Posted (Actual): October 3, 2017

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: CHF; HF; Cardiac dysfunction; acute heart failure; congestive heart failure; chronic heart failure; Left ventricular hypertrophy; LVEF; Heart failure with reduced left ventricular ejection fraction; Heart muscle dysfunction; Left ventricular (LV) dilation; AHF; CCF; congestive cardiac failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696BFI03; 2017-002113-64 (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