Repetitive Levosimendan Infusion for Patients With Advanced Chronic Heart Failure (LeoDOR)

Repetitive levosimendan infusions for patients with advanced chronic heart failure (LeoDOR) A randomised, double-blind, placebo-controlled multicentre study with parallel group design.

Mortality and rehospitalisation rates are high in the vulnerable phase following heart failure hospitalisation. Previous studies suggest that these events can be reduced by repeat infusions of levosimendan in patients with advanced heart failure.

Study Overview

• Status: Unknown
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Levosimendan 2.5 MG/ML; Drug: Placebos

• Study Type: Interventional
• Enrollment (Anticipated): 264
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
      • Recruiting
      • Medical University Innsbruck
      • Contact: Kathrin Becker, PhD; Phone Number: 844 +43512900371; Email: leodor@i-med.ac.at
      • Contact: Sabine Embache-Aichhorn; Phone Number: 086 +43512900370; Email: leodor@i-med.ac.at

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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 by 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 after recompensation of more or equal 2500 ng/L (BNP more or equal 900 ng/L) and/or NYHA class III or IV at study entry

Exclusion 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 a/o 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) <30 ml/min/1.73m2)
12. Anaemia (haemoglobin < 10 g/dl)
13. Significant hepatic impairment at the discretion of the investigator.
14. Hypersensitivity to levosimendan
15. Other serious diseases limiting life expectancy considerably (e.g. end-stage cancer, 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 woman and nursing mother
20. Failure to use highly-effective (Pearl Index lower than 1%) contraceptive methods.
21. Person with any kind of dependency on the investigator
22. Person held in an institution by legal or official order

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levosimendan Arm; Patients receive 6 or 24 hours infusion depending on the site. Levosimendan 2.5 MG/M 6h infusion group: 0,2 μg/kg/min 7 times (day 0, 14, 28, 42, 56, 70, 84) Levosimendan 24h infusion group: 0,1 μg/kg/min 5 times (day 0, 21,42,63,84) Levosimendan	Drug: Levosimendan 2.5 MG/ML; Levosimendan Arm: 1 x 5 ml (1 vial) of levosimendan infusion concentrate is added to one 250 ml infusion bag of 5% glucose or 0.9% NaCl in diabetic patients.; Other Names: Simdax, Orion Pharma, Espoo, Finland
Placebo Comparator: Placebo Arm; Patients receive 6 or 24 hours infusion depending on the site. 6h infusion group: 0,2 μg/kg/min 7 times (day 0, 14, 28, 42, 56, 70, 84) Placebo 24h infusion group: 0,1 μg/kg/min 5 times (day 0, 21,42,63,84) Placebo	Drug: Placebos; Placebo Arm: 1 x 5 ml (1 vial) of placebo levosimendan infusion concentrate is added to one 250 ml infusion bag of 5% glucose or 0.9% NaCl in diabetic patients.; Other Names: Placebo Levosimendan infusion concentrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to death, high-urgent heart transplantation or ventricular assist device (VAD), time to non-fatal HF event	Time to event in days, from baseline visit (day 1) up to Follow-up 2 (day 180)	From baseline (day 1) up to Follow-up 2 (day 180)
Change in NT-proBNP	pg/ml	Change from Baseline NT-proBNP (day 1) to Follow-up 1 (day 90)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in functional status and symptoms via KCCQ (Combined Outcome measurement)	KCCQ (Kansas City Cardiomyopathy Questionnaire) The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.	From baseline (day 1) up to day 98 (FUP 1)
Change in functional status and symptoms via PGA (Combined Outcome measurement)	PGA (Patient's global assessment)	From baseline (day 1) up to day 98 (FUP 1)
Change in functional status and symptoms via EQ-5D-5L (Combined Outcome measurement)	EQ-5D-5L VAS is a standardised measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal visual analogue scale	From baseline (day 1) up to day 98 (FUP 1)
cumulative number of: days alive out of hospital (Combined Outcome measurement)	Counted in days	From baseline (day 1) up to day 180 (FUP 2)
cumulative number of: non-fatal HF events (Combined Outcome measurement)	Counted in events	From baseline (day 1) up to day 180 (FUP 2)
cumulative number of: hospital admissions (Combined Outcome measurement)	counted in numbers	From baseline (day 1) up to day 180 (FUP 2)
death	Number of participants died within the defined time points	From baseline (day 1) to day 180 (FUP 2)
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 counted in numbers	From baseline (day 1) to day 180 (FUP 2)

Collaborators and Investigators

• Sponsor: Dr. Gerhard Pölzl
• Collaborators: Orion Corporation, Orion Pharma

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2018
• Primary Completion (Anticipated): April 1, 2019
• Study Completion (Anticipated): December 31, 2019

Study Registration Dates

• First Submitted: October 9, 2017
• First Submitted That Met QC Criteria: February 12, 2018
• First Posted (Actual): February 19, 2018

Study Record Updates

• Last Update Posted (Actual): August 22, 2018
• Last Update Submitted That Met QC Criteria: August 20, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Heart Failure, Levosimendan
• 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: LeoDOR2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No