Cardiogenic ShockMILADECMONCT06993584
Pharmacokinetic Modelling of Levosimendan in Adults
An observational study of Cardiogenic Shock, run by University Hospital, Rouen at 3 sites in France.
Trial summary
In the light of current knowledge of the PK of levosimendan and its use in ECMO weaning, deciphering the mechanisms of inter-individual variability in exposure and response to levosimendan appears essential in order to better stratify patients eligible or not for this therapy and to adapt the treatment of patients in… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Cardiogenic Shock
- What is being tested?
- Adult patients in cardiogenic shock
- How many people
- 100 participants
- Where
- 3 sitesFrance
- Study dates
- 1 Jul 2025to 31 Aug 2027
- How long will I take part?
- 28 Months
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients treated with Lévosimendan (LVSMD) as part of their usual care for cardiogenic shock (60 with extracorporeal membrane oxygenation (ECMO) and 40 without ECMO)
Who may be able to join
- Patient between 18 and 75 years of age admitted to an intensive care unit,
- Weight ≥ 50 kg,
- Patient with cardiogenic shock defined by a SCAI stage C, D, or E score.
- The medical team plans to initiate LVSMD treatment as part of the management of cardiogenic shock, according to the recommendations in the Summary of Product Characteristics (SmPC),
- Expected life expectancy > 48 hours,
- Patient affiliated with a social security scheme,
- Due to the life-threatening nature of cardiogenic shock, the patient or, where applicable, family members or trusted person are informed as soon as possible and their consent is requested for the possible continuation of this research. They may also object to the use of the patient's data (and blood samples) for this research.
Who cannot join
- Pregnant, childbearing, or breastfeeding women,
- Persons deprived of their liberty by an administrative or judicial decision, or persons placed under judicial protection/guardianship or curatorship.
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
France3 sites
Cardio-Thoracic-Vascular Resuscitation Department, university Hospital of Amiens
Amiens, 80054
Abouarab AO OSAMA, Doctor, 03 22 08 79 89 ext. +33, abouarab.osama@chu-amiens.fr
Anesthesia Clinic - Resuscitation, University Hospital of Lile
Lille, 59037
Mouhamed MM MOUSSA, Doctor, 03 20 44 59 62 ext. +33, mouhamed.moussa@chru-lille.fr
Anesthesia-Resuscitation Department, University Rouen Hospital
Rouen, 76031
Camille CM MOLKHOU, Doctor, 02 32 88 78 42 ext. +33, camille.molkhou@chu-rouen.fr
About this study
Official title: Pharmacokinetic Modelling of Levosimendan in Adults in Cardiogenic Shock With or Without Extracorporeal Membrane Oxygenation Support
In the light of current knowledge of the PK of levosimendan and its use in ECMO weaning, deciphering the mechanisms of inter-individual variability in exposure and response to levosimendan appears essential in order to better stratify patients eligible or not for this therapy and to adapt the treatment of patients in cardiogenic shock, with or without ECMO support, accordingly. The aim of this project is to use an innovative pharmacokinetic modelling approach based on clinico-biological data to study the key factors that could contribute to treatment failure in cardiogenic shock and to integrate them quantitatively for dose individualisation. The aim of this project is to conduct a prospective, multicentre, observational, comparative analysis, with minimal risks and constraints, to determine the concentrations of levosimendan and its metabolites during patient management in order to develop a pharmacokinetic model.
Read the detailed description
Cardiogenic shock is a pathological condition characterised by cardiac failure inducing tissue hypoxia and organ hypoperfusion, which can lead to multiple organ failure and death. Extracorporeal membrane oxygenation (ECMO) is a circulatory support technique commonly used in the treatment of cardiogenic shock. This device reduces mortality in patients with refractory shock, i.e. those who do not respond, or only partially respond, to medical treatment including inotropic and vasopressor pharmacological support. ECMO is associated with significant pharmacokinetic (PK) changes related to volume of distribution (Vd) and clearance (CL), which may alter the efficacy of treatments. From a PK point of view, the addition of an extracorporeal circuit capable of sequestering and/or degrading drugs represents a challenge for dose adjustment. Levosimendan (LVSMD) is a drug authorised for the treatment of acute decompensated heart failure. It's a lipophilic drug (logP=2.16) and highly protein-bound (>97%), two properties that favour its sequestration in the ECMO circuit [2]. This hypothesis is reinforced by the recent publication of a RIPH3 study evaluating the PK of levosimendan in neonates and children in intensive care, whether or not assisted by ECMO (NCT03681379, Bourgoin P, Duflot T, Clin Pharmacokinet). The rationale for this project is based on the following hypotheses: 1°) Beneficial effects on renal function, pulmonary congestion, physical capacity and cardiac output have been observed with levosimendan in the management of cardiogenic shock [4] 2°) The use of antibiotics could alter the metabolism of LVSMD leading to a defect in the synthesis of the active metabolite. 3°) LVSMD is beneficial during weaning from ECMO and the contradictions in previously published results [5] could be attributed to a reduced half-life of the drug and/or OR-1896 due to adsorption phenomena on the ECMO circuit making the treatment less effective.
- Conditions
- Cardiogenic Shock
- Being tested
- Adult patients in cardiogenic shock
- Keywords
- cardiogenic shock, levosimendan, pharmacokinetics, ECMO, extracorporeal membrane oxygenation, ECLS
- Medical subject headings
- Shock, Cardiogenic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Adult patients in cardiogenic shockOther
evaluate the elimination clearance of levosimendan (LVSMD) in the group without extracorporeal membrane oxygenation (ECMO) and in the group with ECMO.
What is being measured
The primary outcome is the main question the study is designed to answer.
Elimination Clearance of Levosimendan (LVSMD) in Adult Patients in Cardiogenic Shock with Extracorporeal Membrane Oxygenation (ECMO)
The clearance (CL) of Lévosimendan (LVSMD) will be determined by the ratio of the total dose administered to the exposure characterised by the area under the curve (AUC) over time (CL=Dose/AUC). In order to obtain an accurate estimate of the AUC, blood samples will be taken from a catheter already in place for the patient's therapeutic needs and will be taken at 0, 2, 6, 24, 26 and 32 hours after the start of an intravenous infusion of LVSMD at the dosage defined according to the recommendations in the Summary of Product Characteristics (SmPC).
Measured: At enrollment visit, hour 1, 2 and 6 and at hour 24, 26 and 32 after enrollment visit
Secondary outcomes (4)
Success rate of weaning in the ECMO patient group
The success rate in the extracorporeal membrane oxygenation (ECMO) group will be assessed by the proportion of patients weaned from ECMO within 72 hours of the end of the levosimendan (LVSMD) infusion. ECMO weanability is assessed according to the Extracorporeal Life Support Organization (ELSO) guidelines by a weaning test, initiated after myocardial recovery, defined by a reduction in amine requirements to a minimum threshold to achieve a mean arterial pressure (MAP) > 65 mmHg with an ECMO flow rate less than 2.5 L/min, usually performed for ECMO weaning. The weaning test is performed under an ECMO flow rate of 1L/min for 3 to 5 minutes, and is a success if the following parameters are obtained under low doses of amines: subaortic ITV > 12 cm/s, LVEF > 25-30%, absence of right ventricular dysfunction, central venous pressure < 10 mmHg and MAP > 60 mmHg
Measured: Hour 72 after enrollment visit
Hemodynamic success rate in the group without extracorporeal membrane oxygenation (ECMO)
he success rate in the group without extracorporeal membrane oxygenation (ECMO) will be assessed by the proportion of patients with an increase in cardiac index of at least 20% associated with venous oxygen saturation > 65% within 72 hours following the end of the levosimendan (LVSMD) infusion, and/or improvement in hemodynamics (normalization of SvO2 and cardiac index > 2.2 L/min/m2 without increase or introduction of dobutamine).
Measured: Hour 72 after enrollment visit
Population-based pharmacokinetic model of LVSMD and its metabolites
The population-based PK model, based on the results of the pediatric population study, will use a two-compartment model with first-order elimination for Lévosimendan (LVSMD). The appearance of metabolites will be modeled by transit compartments and their elimination will follow first-order kinetics. The collected clinical-biological data will be evaluated as covariates or as regressors (for time-dependent variables). Pharmacokinetic parameters will be evaluated according to a lognormal distribution (solutions > 0) and regressors according to a normal distribution. Pharmacokinetic parameters will be calculated in a global structural population model and individual parameters will be determined by Bayesian estimation. The final model will then be used to perform simulations to establish the dosage allowing similar exposure between patients supported by extracorporeal membrane oxygenation (ECMO) and patients without extracorporeal membrane oxygenation (ECMO) during cardiogenic shock.
Measured: Hours 48, 72, 96, 120, 144, 168, 336 and 504 after enrollment visit
Influence of a change in intestinal microbiota on the conversion of levosimendan into its active metabolite
Given the metabolism of levosimendan to OR1896 by intestinal microbiota described in numerous studies, it seems legitimate to wonder whether inter-individual variability in response to treatment might not be linked to individual changes in intestinal microbiota. The aim is therefore to characterize the intestinal microbiota by swabbing and bioinformatic analysis, and to determine whether there are responder or non-responder profiles.
Measured: Two rectal swabs 24 hours apart, one at enrollment visit and one at hour 24 after enrollment visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2025
- Study start1 Jul 2025 (estimated)
- Primary completion30 Jul 2027 (estimated)
- Study completion31 Aug 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cardiogenic ShockStudies of the same condition, open and under way.
- More trials run by University Hospital, RouenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
- Target duration
- 28 Months
Sponsor and investigators
- Lead sponsor
- University Hospital, Rouen
- Sponsor type
- University, hospital or other
- Collaborators
- University Hospital, Lille, Amiens University Hospital, France
- Responsible party
- Sponsor
- Investigators
- Thomas TD DUFLOT, PharmD, Study chair, pharmacology department, University Hospital of RouenEmmanuel BESNIER, MD, PHD, Study chair, anesthesiology, University Hospital of Rouen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06993584
- Sponsor's protocol ID
- 2022/0346/HP
- Other IDs
- 2025-A00556-43
- Acronym
- MILADECMO
- Status last verified
- Apr 2025
- First submitted
- 19 May 2025
- Last updated
- 27 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: The data provided will be the property of the sponsor and will be used solely for its own research activities.
Study at a glance
From the registry record, last updated by the sponsor on 27 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetic Modelling of Levosimendan in Adults in Cardiogenic Shock With or Without Extracorporeal Membrane Oxygenation Support
- ClinicalTrials.gov ID
- NCT06993584
- Acronym / sponsor ID
- MILADECMO / 2022/0346/HP
- Conditions
- Cardiogenic Shock
- Keywords
- cardiogenic shock, levosimendan, pharmacokinetics, ECMO, extracorporeal membrane oxygenation, ECLS
- Study type
- Observational
- Recruitment status
- Not yet recruiting
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- University Hospital, RouenUniversity, hospital or other
- Collaborators
- University Hospital, Lille, Amiens University Hospital, France
- Study start
- 1 Jul 2025 (estimated)
- Primary completion
- 30 Jul 2027 (estimated)
- Study completion
- 31 Aug 2027 (estimated)
- First posted
- 29 May 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In the light of current knowledge of the PK of levosimendan and its use in ECMO weaning, deciphering the mechanisms of inter-individual variability in exposure and response to levosimendan appears essential in order to better stratify patients eligible or not for this therapy and to adapt the treatment of patients in cardiogenic shock, with or without ECMO support, accordingly. The aim of this project is to use an innovative pharmacokinetic modelling approach based on clinico-biological data to study the key factors that could contribute to treatment failure in cardiogenic shock and to integrate them quantitatively for dose individualisation. The aim of this project is to conduct a prospective, multicentre, observational, comparative analysis, with minimal risks and constraints, to determine the concentrations of levosimendan and its metabolites during patient management in order to develop a pharmacokinetic model.
Detailed description
Cardiogenic shock is a pathological condition characterised by cardiac failure inducing tissue hypoxia and organ hypoperfusion, which can lead to multiple organ failure and death. Extracorporeal membrane oxygenation (ECMO) is a circulatory support technique commonly used in the treatment of cardiogenic shock. This device reduces mortality in patients with refractory shock, i.e. those who do not respond, or only partially respond, to medical treatment including inotropic and vasopressor pharmacological support. ECMO is associated with significant pharmacokinetic (PK) changes related to volume of distribution (Vd) and clearance (CL), which may alter the efficacy of treatments. From a PK point of view, the addition of an extracorporeal circuit capable of sequestering and/or degrading drugs represents a challenge for dose adjustment. Levosimendan (LVSMD) is a drug authorised for the treatment of acute decompensated heart failure. It's a lipophilic drug (logP=2.16) and highly protein-bound (>97%), two properties that favour its sequestration in the ECMO circuit [2]. This hypothesis is reinforced by the recent publication of a RIPH3 study evaluating the PK of levosimendan in neonates and children in intensive care, whether or not assisted by ECMO (NCT03681379, Bourgoin P, Duflot T, Clin Pharmacokinet). The rationale for this project is based on the following hypotheses: 1°) Beneficial effects on renal function, pulmonary congestion, physical capacity and cardiac output have been observed with levosimendan in the management of cardiogenic shock [4] 2°) The use of antibiotics could alter the metabolism of LVSMD leading to a defect in the synthesis of the active metabolite. 3°) LVSMD is beneficial during weaning from ECMO and the contradictions in previously published results [5] could be attributed to a reduced half-life of the drug and/or OR-1896 due to adsorption phenomena on the ECMO circuit making the treatment less effective.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Target follow-up
- 28 Months
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients treated with Lévosimendan (LVSMD) as part of their usual care for cardiogenic shock (60 with extracorporeal membrane oxygenation (ECMO) and 40 without ECMO)
Key inclusion criteria (7 listed)
- Patient between 18 and 75 years of age admitted to an intensive care unit,
- Weight ≥ 50 kg,
- Patient with cardiogenic shock defined by a SCAI stage C, D, or E score.
- The medical team plans to initiate LVSMD treatment as part of the management of cardiogenic shock, according to the recommendations in the Summary of Product Characteristics (SmPC),
- Expected life expectancy > 48 hours,
Key exclusion criteria (2 listed)
- Pregnant, childbearing, or breastfeeding women,
- Persons deprived of their liberty by an administrative or judicial decision, or persons placed under judicial protection/guardianship or curatorship.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Adult patients in cardiogenic shockevaluate the elimination clearance of levosimendan (LVSMD) in the group without extracorporeal membrane oxygenation (ECMO) and in the group with ECMO. | Other | – |
Primary outcome
Elimination Clearance of Levosimendan (LVSMD) in Adult Patients in Cardiogenic Shock with Extracorporeal Membrane Oxygenation (ECMO)
Time frame: At enrollment visit, hour 1, 2 and 6 and at hour 24, 26 and 32 after enrollment visit
The clearance (CL) of Lévosimendan (LVSMD) will be determined by the ratio of the total dose administered to the exposure characterised by the area under the curve (AUC) over time (CL=Dose/AUC). In order to obtain an accurate estimate of the AUC, blood samples will be taken from a catheter already in place for the patient's therapeutic needs and will be taken at 0, 2, 6, 24, 26 and 32 hours after the start of an intravenous infusion of LVSMD at the dosage defined according to the recommendations in the Summary of Product Characteristics (SmPC).
4 secondary outcomes
Success rate of weaning in the ECMO patient group
Time frame: Hour 72 after enrollment visit
Hemodynamic success rate in the group without extracorporeal membrane oxygenation (ECMO)
Time frame: Hour 72 after enrollment visit
Population-based pharmacokinetic model of LVSMD and its metabolites
Time frame: Hours 48, 72, 96, 120, 144, 168, 336 and 504 after enrollment visit
Influence of a change in intestinal microbiota on the conversion of levosimendan into its active metabolite
Time frame: Two rectal swabs 24 hours apart, one at enrollment visit and one at hour 24 after enrollment visit
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jun 2025.
- Individual participant dataSharing planned: No. The data provided will be the property of the sponsor and will be used solely for its own research activities.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Thomas TD DUFLOT, PharmD study chair
pharmacology department, University Hospital of Rouen
Emmanuel BESNIER, MD, PHD study chair
anesthesiology, University Hospital of Rouen
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Cardiogenic Shock, run by University Hospital, Rouen at 3 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 27 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Camille MOLKHOU, MD (02 32 88 78 42 ext. +33, camille.molkhou@chu-rouen.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Elimination Clearance of Levosimendan (LVSMD) in Adult Patients in Cardiogenic Shock with Extracorporeal Membrane Oxygenation (ECMO) (time frame: At enrollment visit, hour 1, 2 and 6 and at hour 24, 26 and 32 after enrollment visit). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jun 2025.