Clinical trial NCT03576677: Effect of Levosimendan or Placebo on Exercise in Advanced Chronic Heart Failure
Official title: Effect of Levosimendan or Placebo on Exercise Capacity and Hemodynamics in Patients With Advanced Chronic Heart Failure (LOCO-CHF Trial)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Heart Failure
Keywords: Advanced chronic heart failure
Exercise capacity
Exercise hemodynamics
Levosimendan
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Orion Corporation, Orion Pharma
First posted: 2018-07-03
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a prospective multi-center, double-blinded, placebo controlled, randomized study in patients with advanced chronic heart failure. Patients who meet the eligibility criteria will be randomized in a 1:1 ratio for treatment with 6 hours infusion of either (i) levosimendan 0.2 µg/kg/min or (ii) placebo (sterile 5% dextrose).

At baseline an upright ergometer maximal exercise test is performed to determine max workload and pVO2 (Test 0). Based on this test 50% of pVO2 with corresponding workload (watt) is calculated (submax).

At Day 0 patients will perform a supine ergometer maximal exercise test (Test 1) with simultaneous invasive hemodynamic measurement by Swan-Ganz catheter. Subsequently, patients will receive 6 hours infusion of study medication.

At Day 5 (4-6 days after infusion of study medication) patients will repeat the supine ergometer maximal exercise test (Test 2) with simultaneous invasive hemodynamic measurements.
Primary purpose: TREATMENT

Brief summary: Purpose: This study evaluates the subacute effect of levosimendan infusion on exercise capacity and exercise hemodynamics compared with placebo in patients with advanced chronic heart failure.

Hypothesis: Treatment with 6 hours infusion of levosimendan compared with placebo improves exercise capacity and exercise hemodynamics evaluated by change in CO/PCWP.

Design: The study is a prospective multi-center, double-blinded, placebo controlled randomized study. 42 consecutive patients who meet the eligibility criteria will be enrolled.

Detailed description: Background: Patients with advanced heart failure (HF) symptoms (NYHA III-IV) have poor quality of life and significantly impaired functional capacity despite optimal medical management. Exercise intolerance in HF results from multiple pathophysiological processes, but central hemodynamics during exercise are important determinants. In patients with advanced HF, intermittent levosimendan infusion is sometimes used to relieve symptoms and possibly improve prognosis. A short-term effect of levosimendan infusion on exercise capacity has previously been reported. However, the underlying mechanisms behind such an improvement, as well as more durable effects of levosimendan on exercise capacity in advanced chronic HF, have not been clearly established. Also the hemodynamic effect of levosimendan has not been investigated in advanced chronic HF during exercise.

To our knowledge no previous studies have evaluated the subacute effect of levosimendan infusion on exercise capacity and exercise hemodynamics in patients with advanced chronic HF. This study will hopefully improve the understanding of the role of levosimendan in the management of these patients.

Purpose: This study evaluates the subacute effect of levosimendan infusion on exercise capacity and exercise hemodynamics compared with placebo in patients with advanced chronic HF.

Hypothesis: Treatment with 6 hours infusion of levosimendan 0.2 µg/kg/min compared with placebo improves exercise capacity and exercise hemodynamics evaluated by change in CO/PCWP (Day 0 to Day 5 (4-6) after infusion) in patients with advanced chronic HF.

Design: The study is a prospective multi-center, double-blinded, placebo controlled randomized study. The study population will consist of 42 consecutive patients who meet the eligibility criteria. Patients will be randomized 1:1 to treatment with either levosimendan or placebo.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* NYHA III-IV on optimal medical treatment
* LVEF ≤35%
* NT-proBNP \>600 µg/L
* pVO2 \<20 mL/kg/min
* No hospitalization for HF or change in loop diuretic \<2 weeks

Exclusion Criteria:

* Recent or acute coronary and respiratory syndromes
* Recent sustained ventricular tachycardia or ventricular fibrillation
* Severe aortic or mitral valve disease
* Known malfunctioning artificial heart valve
* Uncorrected obstructive valvular disease
* Hypertrophic cardiomyopathy
* Fertile women
* Uncorrected thyroid disease
* Presence of any disease/condition that might per se influence exercise performance
* Left ventricular assist device
* Pacemaker-guided heart rate at rest or during exercise
* Known contraindication for treatment with levosimendan
* Any treatment with levosimendan in the previous 6 months
* Inability to perform a VO2max test
* Symptomatic hypotension or systolic blood pressure \< 90 mmHg

Primary outcomes:
measure: ΔCO/PCWP (submax)
timeFrame: Day 0 to Day 5 (4-6)
Secondary outcomes:
measure: ΔCO/PCWP (peak)
timeFrame: Day 0 to Day 5 (4-6)
measure: ΔCO (peak)
timeFrame: Day 0 to Day 5 (4-6)
measure: ΔPCWP (peak)
timeFrame: Day 0 to Day 5 (4-6)
measure: CO maximal
timeFrame: Day 5
measure: PCWP maximal
timeFrame: Day 5
measure: SvO2 maximal
timeFrame: Day 5
measure: Workload maximal
timeFrame: Day 5
measure: ΔPCWP (rest)
timeFrame: Day 0 to Day 5 (4-6)
measure: ΔCO (rest)
timeFrame: Day 0 to Day 5 (4-6)
measure: ΔCVP (rest)
timeFrame: Day 0 to Day 5 (4-6)
measure: ΔmPA (rest)
timeFrame: Day 0 to Day 5 (4-6)
measure: ΔSvO2 (rest)
timeFrame: Day 0 to Day 5 (4-6)
measure: Δ6MWT day 3
timeFrame: Day 0 to Day 3
measure: Δ6MWT day 5 (4-6)
timeFrame: Day 0 to Day 5 (day 4-6)
measure: Δ6MWT day 14
timeFrame: Day 0 to Day 14
measure: ΔNT-proBNP day 3
timeFrame: Day 0 to Day 3
measure: ΔNT-proBNP day 5
timeFrame: Day 0 to Day 5 (day 4-6)
measure: ΔNT-proBNP day 14
timeFrame: Day 0 to Day 14
measure: QOL day 3
timeFrame: Day 3
measure: QOL day 5
timeFrame: Day 5
measure: QOL Day 14
timeFrame: Day 14
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Department of Cardiology, The Heart Center, Copenhagen University Hospital, Rigshospitalet
city: Herlev
country: Denmark
facility: Department of Cardiology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark
city: Odense
country: Denmark
facility: Department of Cardiology, Odense University Hospital, Odense, Denmark
Study officials:
affiliation: Department of Cardiology, The Heart Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
name: Finn Gustafsson, MD, professor, PhD, DMSci
role: PRINCIPAL_INVESTIGATOR
References: