Effect of Levosimendan or Placebo on Exercise in Advanced Chronic Heart Failure (LOCO-CHF)

Effect of Levosimendan or Placebo on Exercise Capacity and Hemodynamics in Patients With Advanced Chronic Heart Failure (LOCO-CHF Trial)

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.

Study Overview

• Status: Unknown
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Levosimendan; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Finn Gustafsson, MD, professor, PhD, DMSci; Phone Number: +45 35459743; Email: finng@dadlnet.dk
• Study Contact Backup: Name: Mikael K Poulsen, MD PhD; Phone Number: +45 24798402; Email: mikael.kjaer.poulsen1@rsyd.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Recruiting
    • Department of Cardiology, The Heart Center, Copenhagen University Hospital, Rigshospitalet
    • Contact: Lærke Nelson, MD; Phone Number: +45 35459549; Email: laerke.marie.nelson@regionh.dk
    • Contact: Finn Gustafsson, MD, professor, PhD, DMSci; Phone Number: +45 35459743; Email: finng@dadlnet.dk
    • Principal Investigator: Finn Gustafsson, MD, professor, PhD, DMSci
    • Sub-Investigator: Lærke Nelson, MD
  • Herlev, Denmark, DK-2730
    • Recruiting
    • Department of Cardiology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark
    • Contact: Morten Schou, MD, PhD; Phone Number: +45 40523920; Email: schou@dadlnet.dk
    • Principal Investigator: Morten Schou, MD, PhD
  • Odense, Denmark, DK-5000
    • Recruiting
    • Department of Cardiology, Odense University Hospital, Odense, Denmark
    • Contact: Jacob E Møller, MD, professor, PhD, DMSci; Phone Number: +45 51439630; Email: jem@dadlnet.do
    • Contact: Mikael K Poulsen, MD, PhD; Phone Number: +45 24798402; Email: mikael.kjaer.poulsen1@rsyd.dk
    • Principal Investigator: Jacob E Møller, MD, professor, PhD, DMSci
    • Sub-Investigator: Mikael K Poulsen, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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
Active Comparator: Levosimendan; Study participants in this arm will receive a 6 hours infusion of levosimendan 0.2 µg/kg/min.	Drug: Levosimendan; Levosimendan, 2.5 mg/mL concentrate for dilution. 5 mL of the study drug will be injected into a 245 mL isotonic glucose solution. Patients will receive a 6 hours infusion of this study drug at an infusion rate of 0.2 µg/kg/min.; Other Names: Simdax
Placebo Comparator: Placebo; Study participants in this arm will receive a 6 hours infusion of placebo (sterile isotonic sodium chloride + 5% dextrose + vitamin B)	Drug: Placebo; The placebo solution will be prepared by adding 10 mL of 5% dextrose to a vial containing Soluvit (vitamin B) under aseptical conditions. 5 mL of this solution is then added to 245 mL of isotonic sodium chloride solution. 5% dextrose and vitamin B are added to ensure yellow coloring indistinguishable from the active drug (levosimendan). Patients will receive a 6 hours infusion of this study drug. Infusion rate will be calculated in similar fashion to the levosimendan group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ΔCO/PCWP (submax)	Change in CO/PCWP from Day 0 (infusion of study medication) to Day 5 (day 4-6) at the workload corresponding to 50% of pVO2 determined at baseline	Day 0 to Day 5 (4-6)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ΔCO/PCWP (peak)	Change in CO/PCWP from Day 0 (infusion of study medication) to Day 5 (day 4-6) at peak exercise	Day 0 to Day 5 (4-6)
ΔCO (peak)	Change in maximal CO from Day 0 (infusion of study medication) to Day 5 (day 4-6) at peak exercise	Day 0 to Day 5 (4-6)
ΔPCWP (peak)	Change in PCWP from Day 0 (infusion of study medication) to Day 5 (day 4-6) at the maximal load obtained during both invasive measurements	Day 0 to Day 5 (4-6)
CO maximal	Maximal CO at Day 5 (day 4-6)	Day 5
PCWP maximal	Maximal PCWP at Day 5 (day 4-6)	Day 5
SvO2 maximal	Maximal SvO2 at Day 5 (day 4-6)	Day 5
Workload maximal	Maximal workload (watt) at Day 5 (day 4-6)	Day 5
ΔPCWP (rest)	Change in resting PCWP from Day 0 (infusion of study medication) to Day 5 (day 4-6)	Day 0 to Day 5 (4-6)
ΔCO (rest)	Change in resting CO from Day 0 (infusion of study medication) to Day 5 (day 4-6)	Day 0 to Day 5 (4-6)
ΔCVP (rest)	Change in resting CVP from Day 0 (infusion of study medication) to Day 5 (day 4-6)	Day 0 to Day 5 (4-6)
ΔmPA (rest)	Change in resting mPA from Day 0 (infusion of study medication) to Day 5 (day 4-6)	Day 0 to Day 5 (4-6)
ΔSvO2 (rest)	Change in resting SvO2 from Day 0 (infusion of study medication) to Day 5 (day 4-6)	Day 0 to Day 5 (4-6)
Δ6MWT day 3	Change in 6MWT from Day 0 (infusion of study medication) to Day 3	Day 0 to Day 3
Δ6MWT day 5 (4-6)	Change in 6MWT from Day 0 (infusion of study medication) to Day 5 (day 4-6)	Day 0 to Day 5 (day 4-6)
Δ6MWT day 14	Change in 6MWT from Day 0 (infusion of study medication) to Day 14	Day 0 to Day 14
ΔNT-proBNP day 3	Change in NT-proBNP from Day 0 (infusion of study medication) to Day 3	Day 0 to Day 3
ΔNT-proBNP day 5	Change in NT-proBNP from Day 0 (infusion of study medication) to Day 5 (day 4-6)	Day 0 to Day 5 (day 4-6)
ΔNT-proBNP day 14	Change in NT-proBNP from Day 0 (infusion of study medication) to Day 14	Day 0 to Day 14
QOL day 3	Quality of life (QOL) score using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at Day 3 after infusion of study medication	Day 3
QOL day 5	Quality of life (QOL) score using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at Day 5 (4-6) after infusion of study medication	Day 5
QOL Day 14	Quality of life (QOL) score using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at Day 14 after infusion of study medication	Day 14

Collaborators and Investigators

• Sponsor: Finn Gustafsson
• Collaborators: Orion Corporation, Orion Pharma
• Investigators: Principal Investigator: Finn Gustafsson, MD, professor, PhD, DMSci, Department of Cardiology, The Heart Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2019
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): July 30, 2020

Study Registration Dates

• First Submitted: June 11, 2018
• First Submitted That Met QC Criteria: June 21, 2018
• First Posted (Actual): July 3, 2018

Study Record Updates

• Last Update Posted (Actual): July 17, 2019
• Last Update Submitted That Met QC Criteria: July 15, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Levosimendan; Exercise capacity; Advanced chronic heart failure; Exercise hemodynamics
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: RH-HJE-LN-02

Drug and device information, study documents

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