Repetitive Levosimendan infusions for patients with advanced chronic heart failure

A randomized, double-blind, placebo-controlled multicenter study with parallel group design.

About the trial

Heart failure (HF) is the leading cause of adult hospitalization in the industrialized world and imposes a substantial burden on the public health. The later stages of heart failure are characterized by a steady decline in quality of life and frequent re-hospitalization for recurrent acutization of the symptoms (Fruhwald 2016).

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Most of the re-hospitalisations take place relatively soon after discharge from the index hospitalisation. About one quarter of patients are re-hospitalized within one month, and more than 60% of these re-hospitalisations are seen within 15 days after discharge (Dharmarajan 2013).

Therapeutic options are limited and drugs used for chronic heart failure often have to be withdrawn owing to side effects such as hypotension or worsening of renal function. As prognosis deteriorates and treatment options become restricted clinical priorities should be recast to emphasize maintaining functional capacity and quality of life (Fruhwald 2016).

Several clinical studies have been performed on the repetitive use of intravenous levosimendan. Their results are suggesting that repeated infusions of levosimendan bring advantages to patients with advanced chronic heart failure. However, some of these studies were open-label, single-center studies and even the largest double-blind studies included a limited number of patients. Therefore, a larger study would be needed to verify the favorable results.

In the LEODOR study the efficacy and safety of intermittent levosimendan therapy started during the vulnerable phase after a recent hospitalisation for heart failure is tested. The over-arching hypothesis of the study is that, compared with placebo, repetitive administration of levosimendan in the post-acute heart failure syndrome discharge period, will be associated with greater clinical stability through 14 weeks as assessed by a composite clinical endpoint consisting of mortality, acute heart failure episodes and change in natriuretic peptide levels.

References: Fruhwald S et al. Expert Rev Cardiovasc Ther. 2016;14:1335-1347. Dharmarajan K et al. BMJ. 2013 Nov 20;347:f6571

 

For patients

Several clinical studies have been performed on the repetitive use of intravenous levosimendan. Their results are suggesting that repeated infusions of levosimendan bring advantages to patients with advanced chronic heart failure such as fewer re-hospitalizations and lower mortality . However, some of these studies were open-label, single-center studies and even the largest double-blind studies included a limited number of patients. Therefore, a larger study is needed to verify the favorable results.
This study is designed to show whether using a drug called levosimendan in patients with advanced heart failure could produce important benefits by improved symptom control and reduction of acute episodes and acute hospitalizations.
Levosimendan is a drug extensively studied in patients with acute decompensated heart failure. It is a licensed drug for this group of patients in many European countries and elsewhere around the world.
Most of the rehospitalisations take place shortly after an index hospitalisation, during a so called vulnerable period. Therefore, patients with chronic advanced heart failure who have recently experienced worsening heart failure requiring hospitalization are recruited for this study. Patients will be treated with repeated levosimendan infusions for 12 weeks.
All patients enrolled for this study are first invited for a Screening Visit and a Baseline Visit during which the final eligibility is checked. The next visits will be the administration visits for the active drug. The treatment period will be 12 weeks (84 days). In order to work out whether levosimendan does actually work, one third of the patients will be randomly chosen to receive an infusion of a dummy treatment, or placebo. Randomisation thus will be on a 2:1 basis. Moreover, patients will receive either a 24 hours or a 6 hour infusion of the test drug, according to the centers.

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For investigators

To date, 10 clinical studies (of which 7 double blind clinical trials) have been performed on the repetitive use of levosimendan. Their results are univocally consistent with the hypothesis that repeated infusion of levosimendan brings advantages to patients in Advanced Heart Failure. However, only a limited amount of patients were enrolled and a bigger study, properly powered, is warranted.

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Aims

The Leodor Trial objectives are to show that repetitive levosimendan infusions are effective and safe in stabilizing patients with advanced chronic heart failure during a vulnerable period following a recent hospitalization.

The trial

Leodor Trial is multicentre, randomised, double-blind, placebo-controlled study in patients with severe chronic heart failure. Patients will receive either a 6-hour infusion every 2 weeks or a 24-hour infusion every 3 weeks up to 12 weeks, followed by a follow-up visit 1 at week 14 and a follow-up visit 2 at week 26. The study will use a parallel group design.

It has been shown from a large trauma RCT that early treatment for bleeding has better outcomes. This study will also look at laboratory and clinical outcome measures.

Exclusion criteria

Patients will not be included into this study if they meet any of the following criteria:

1
Severe obstruction of ventricular outflow tracts such as haemodynamically significant uncorrected primary valve disease or hypertrophic cardiomyopathy or impaired ventricular filling such as restrictive cardiomyopathy.
2
Predominantly right heart failure and/or severe tricuspid regurgitation.
3
Cardiac surgery or coronary angioplasty within 30 days before study drug initiation.
4
Acute coronary syndrome within 30 days before study drug initiation.
5
Patients who are scheduled for cardiac surgery or angioplasty in the next 3 months.
6
History of torsades de pointes.
7
Stroke or transient ischaemic attack (TIA) within 3 months before study drug initiation.
8
Systolic blood pressure less than 90 mmHg at baseline.
9
Heart rate 120 bpm or greater at baseline.
10
Serum potassium less than 3.5 mmol/l before study drug initiation.
11
Severe renal insufficiency (estimated glomerular filtration rate [eGFR] less than 30 ml/min/1.73m2).
12
Anaemia (haemoglobin less than 10 g/dl).
13
Significant hepatic impairment at discretion of the investigator.
14
Hypersensitivity to levosimendan.
15
Other serious diseases limiting life expectancy considerably (e.g. end-stage cancer, end-stage renal disease, end-stage lung disease).
16
Participation in a clinical trial with any experimental treatment within 30 days prior to screening or previous participation in the present study.
17
Administration of levosimendan within 14 days prior the study drug initiation (the first study drug application has to be postponed for at least 14 days after the end of this premedication).
18
Suspected non-compliance.
19
Pregnant women and nursing mothers.
20
Failure to use highly effective (a Pearl Index lower than 1%) contraceptive methods.
21
Persons with any kind of dependency on the investigator.
22
Persons held in an institution by legal or official order.

Inclusion criteria

Patients must meet all of the following criteria to be included into the study:

1
Written, signed and dated informed consent.
2
Male and female patients over 18 years of age.
3
Women of childbearing potential must have a monthly negative pregnancy test and must refrain from breastfeeding. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be of childbearing potential.
4
CHF diagnosed at least 6 months before screening and treated with individually optimised long-term oral treatment for the last month, unless not tolerated (e.g. ACE-inhibitor or AT II blocker, beta-blocker, mineralocorticoid receptor antagonist, angiotensin II receptor blocker neprilysin inhibitor [ARNI] and with devices [e.g. CRT/ICD], as needed).
5
Left ventricular ejection fraction less than or equal to 30% as assessed using echocardiography, radionuclide ventriculography or contrast angiography within the index hospitalisation.
6
Currently hospitalised for decompensated HF requiring i.v. diuretics, or i.v. vasodilators, or i.v. inotropic therapy, or their combination.
7
Previous hospitalisation or visit to outpatient clinic requiring i.v. diuretics, i.v. vasodilators, or i.v. inotropic therapy, or their combination for acute decompensated HF within 12 months before the current hospitalisation.
8
NT-proBNP level (as measured by the local laboratory) after recompensation of >=2500 ng/L and/or NYHA class III or IV at study entry.

Outcome measures

The primary efficacy objective of the study is to compare the effects of pulsed application of levosimendan versus placebo in patients with advanced chronic heart failure during a vulnerable period of 14 weeks following a recent hospitalisation on a global rank endpoint in which all participants are ranked across three hierarchical groups:

1
time to death or high-urgent heart transplantation or ventricular assist device (VAD)
2
time to non-fatal HF event requiring i.v. vasoactive therapy (i.v. diuretics, i.v. vasodilators or i.v. inotropes) and
3
time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to 14 weeks.

Meet the team

Kathrin Becker

Kathrin Becker

Project Manager - Medical University Innsbruck, Austria

Liane Fendt

Liane Fendt

Project Manager - Medical University Innsbruck, Austria

 

Gerhard Poelzl

Gerhard Pölzl

Leodor Trial Principal Investigator; Chief of the Heart Failure and Heart Transplant Program, Medical University Innsbruck, Austria

Josep Comin-Colet

Josep Comin-Colet

Hospital Universitario de Bellvitge. Barcelona, Spain

Francesco Fedele

Francesco Fedele

"Umberto I" Hospital, "La Sapienza" University, Rome, Italy

Matin Jesus Gonzales

Martin Jesus Gonzales

Hospital Universitario de La Laguna. Tenerife, Spain

Finn Gustafsson

Finn Gustafsson

Copenhagen University Hospital, Copenhagen, Denmark

Josep Masip

Josep Masip

Hospital Sanitas Cima, Barcelona, Spain

Juan F Delgardo

Juan F Delgado

Hospital 12 de Octubre, Madrid, Spain

Stefan Störk

Stefan Störk

University Hospital Würzburg, Würzburg, Germany

Gerhard Wikström

Gerhard Wikström

Akademiska University Hospital, Uppsala, Sweden

Zoltan Papp

Zoltan Papp

Faculty of Medicine, University of Debrecen, Debrecen, Hungary

Bojan Vrtovec

Bojan Vrtovec

University Medical Centre, Ljubljana, Slovenia

Sabine Embacher-Aichhorn

Sabine Embacher

Head, Clinical Studies Coordination Center Medical University Innsbruck, Austria

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