The ECMOCYP (cytochromes P450 Activity) Study

Impact of Temporary Mechanical Circulatory Support (tMCS) on Cytochromes P450 Activity Measured with Dried Blood Spot

Prospective open label observational study including patients requiring a tMCS (VA-ECMO or Impella® CP) or in in cardiogenic shock according to the SCAI (Society for Cardiovascular Angiography and Interventions) ESC (European Society of Cardiology) definition 41,42 and not requiring or not eligible to tMCS (ECMO, Impella®, intra-aortic balloon pump) (control group).

Study Overview

• Status: Recruiting
• Conditions: Cardiogenic Shock; ECMO; Temporary Mechanical Circulatory Support
• Intervention / Treatment: Diagnostic test: phenotype

Detailed Description

The Geneva cocktail will be administered on 2 occasions at D3 after tMCS implantation (or start of the cardiogenic shock) and 14 days after tMCS explantation (or cardiogenic shock termination defined as: no need to use inortropic or vasopressive agent and absence of organ insufficiency)

Primary endpoint:

• Evaluate the impact of tMCS on the activity of CYPs as measured with metabolic ratios MRs (CYP activity at
• D3 post tMCS implantation and 14 days after tMCS explantation vs the activity of CYPs in the control group.

Secondary endpoints:

• Evaluate the correlation between the activity of CYPs and IL-6 levels
• Evaluate the correlation between the activity of CYPs and CRP levels
• Evaluate the correlation between the activity of CYPs and TNF-α levels
• Evaluate the correlation between the activity of CYPs and IL-1β levels
• Evaluate the correlation between the activity of CYPs and IFN-γ levels
• Compare CYP activity vs expected CYP activity based on patients' CYP genotyping
• Compare CYP activity between VA-EMCO and micro-axial pump device (Impella® CP)

• Study Type: Observational
• Enrollment (Estimated): 46

Contacts and Locations

• Study Contact: Name: Jean Terrier, Dr; Phone Number: +41795530888; Email: jean.terrier@hug.ch
• Study Contact Backup: Name: Anastasia Zaslavskaya, Dr; Phone Number: +41795535729; Email: anastasia.zaslavskaya@hug.ch

Study Locations

• Switzerland
  • Geneva, Switzerland, 1205
    • Recruiting
    • University Hospital of Geneva
    • Contact: Jean Terrier, MD; Phone Number: +41795530888; Email: jean.terrier@hug.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

• Male and female patients presenting a refractory cardiogenic shock, requiring temporary mechanical circulatory support (tMCS), with either the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or a micro-axial pump device (Impella® CP).
• Male and female patients in cardiogenic shock according to the SCAI (Society for Cardiovascular Angiography and Interventions) ESC (European Society of Cardiology) definition and not requiring or not eligible to temporary mechanical circulatory support (tMCS). (e.g. ECMO, Impella®, intra-aortic balloon pump) Hospitalised in intensive care unit

Description

Inclusion Criteria:

• Male and female patients presenting a refractory cardiogenic shock, requiring temporary mechanical circulatory support (tMCS), with either the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or a micro-axial pump device (Impella® CP).
• Male and female patients in cardiogenic shock according to the SCAI (Society for Cardiovascular Angiography and Interventions) ESC (European Society of Cardiology) definition and not requiring or not eligible to temporary mechanical circulatory support (tMCS). (e.g. ECMO, Impella®, intra-aortic balloon pump) (control group)
• Age > 18 years old
• Comprehension of French
• Ability to give consent (consent will be sought from the therapeutic representative or from relatives as the patient will be sedated and intubated. Definitive consent will be sought at patient's second blood sample planned after tMCS explantation (in case of patient's favorable outcome).

Exclusion Criteria:

• Male and female patients presenting a refractory ARDS requiring veno-venous extracorporeal membrane oxygenation (VV-ECMO)
• Inability to receive the Geneva cocktail by enteral way
• Severe or terminal Renal impairment (defined as GFR<30ml/min according to Cockroft-Gault)
• Severe chronic hepatic insufficiency (CHILD B-C)
• Sensitivity to any of the drugs used in the Geneva Cocktail
• Intake of drugs altering CYPs activity (Strong inhibitor or inducer based on https://www.hug.ch/sites/hde/files/structures/pharmacologie_et_toxicologie_cliniques/a5_cytochromes_6_2.pdf)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Temporary mechanical circulatory support group; Male and female patients presenting a refractory cardiogenic shock, requiring temporary mechanical circulatory support (tMCS), with either the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or a micro-axial pump device (Impella® CP).	Diagnostic test: phenotype; Eligible patients will receive orally the cocktail probe drugs ( via a naso-gastric tube at D3 after tMCS implantation or after the beginning of the cardiogenic shock for the control group) and via an oral administration at 14 days after tMCS explantation (or cardiogenic shock termination for the control group defined as: no need to use inortropic or vasopressive agent and absence of organ insufficiency). The phenotyping probe drugs of the Geneva Cocktail will be given as: one capsule containing the remaining probe 'cocktail' drugs. According to clinical experience in our intensive care unit department, inflammation related to tMCS peaks at D3 after tMCS implantation. Blood samples will be collected from the central venous line 2 hours after drug administration for CYP phenotyping and genotyping. Inflammatory markers blood levels (Il-6, TNF-α, Il-1β, IFN-γ) will be measured at tMCS implantation or shock initiation and at the same time than CYP phenotyping.; Other Names: CRP; IL-6; TNF-alpha; IFN-γ; IL-1β
Control group; Male and female patients in cardiogenic shock according to the SCAI (Society for Cardiovascular Angiography and Interventions) ESC (European Society of Cardiology) definition and not requiring or not eligible to temporary mechanical circulatory support (tMCS). (e.g. ECMO, Impella®, intra-aortic balloon pump)	Diagnostic test: phenotype; Eligible patients will receive orally the cocktail probe drugs ( via a naso-gastric tube at D3 after tMCS implantation or after the beginning of the cardiogenic shock for the control group) and via an oral administration at 14 days after tMCS explantation (or cardiogenic shock termination for the control group defined as: no need to use inortropic or vasopressive agent and absence of organ insufficiency). The phenotyping probe drugs of the Geneva Cocktail will be given as: one capsule containing the remaining probe 'cocktail' drugs. According to clinical experience in our intensive care unit department, inflammation related to tMCS peaks at D3 after tMCS implantation. Blood samples will be collected from the central venous line 2 hours after drug administration for CYP phenotyping and genotyping. Inflammatory markers blood levels (Il-6, TNF-α, Il-1β, IFN-γ) will be measured at tMCS implantation or shock initiation and at the same time than CYP phenotyping.; Other Names: CRP; IL-6; TNF-alpha; IFN-γ; IL-1β

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the impact of temporary mechanical circulatory support on the activity of CYPs as measured with metabolic ratios MRs (CYP activity at D3 post tMCS implantation and 14 days after tMCS explantation vs the activity of CYPs in the control grou	CYP450 3A4, 2C19, 2D6, 2B6, 1A2 activity will be assessed in using the metabolic ratio of the following probe respectively: midazolam, esomeprazole, dextrometorphan, bupropion and caffein.	During the ECMO

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the correlation between the activity of CYPs and IL-6 levels		During the ECMO
Evaluate the correlation between the activity of CYPs (MRs) and CRP levels		During the ECMO
Evaluate the correlation between the activity of CYPs (MRs) and TNF-α levels		During the ECMO
Evaluate the correlation between the activity of CYPs (MRs) and IL-1β levels		During the ECMO
Evaluate the correlation between the activity of CYPs (MRs) and IFN-γ levels		During the ECMO
Compare CYP activity vs expected CYP activity based on patients' CYP genotyping	CYP phenotyping based classification in metabolizer status (UM, NM, IM or PM) using metabolic ratios will be compared to genotyping based classification from the star allele nomenclature according to Pharmacogene Variation (PharmVar) Consortium. ).	During the ECMO
Compare CYP activity based on phenotyping between VA-EMCO and micro-axial pump device (Impella® CP)	CYP450 CYP3A4, 2C19, 2D6, 2C19, 1A2 activity will be determined as mentionned for the primary issue and will be compared between the groups VA-ECMO and micro-axial pump device	During the ECMO

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Collaborators: Youssef Daali; Jean Terrier; Benjamin Assouline; Raphël Giraud; Karim Bendjelid; Caroline Samer; Anastasia Zaslavskaya

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: September 13, 2024
• First Submitted That Met QC Criteria: October 25, 2024
• First Posted (Actual): October 28, 2024

Study Record Updates

• Last Update Posted (Actual): October 28, 2024
• Last Update Submitted That Met QC Criteria: October 25, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: cardiogenic shock; phenotyping; genotyping; CYP450; ecmo; Temporary Mechanical Circulatory Support; TMCS
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Infarction; Necrosis; Myocardial Ischemia; Myocardial Infarction; Ischemia; Shock; Shock, Cardiogenic
• Other Study ID Numbers: 2023-01398

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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