Copeptin Kinetics in Critically Ill Patients With Posterior Reversible Encephalopathy Syndrome (XPRESSE)

The Arginine Vasopressin aXis as a Potential Therapeutic Target for Posterior REverSible Encephalopathy SyndromE (XPRESSE)

XPRESSE is a multicenter observational prospective biomarker study in which critically ill patients with MRI-based PRES diagnosis will have copeptin kinetics from a daily blood sample for 6 days and a 3-month follow-up. This study aims to investigate the relationship between copeptin and PRES in order to establish the optimal therapeutic time window for vaptan treatment against PRES.

Data collection using an electronic case report form will include demographic data, medical history and data related to PRES: onset modalities and date of symptoms control, radiological features of PRES, biological investigations, results of etiological investigations and therapeutic management (e.g., anticonvulsants, antihypertensive drugs, supportive treatments). Outcomes will include modified Rankin scale score and Glasgow Outcome Scale score at ICU discharge, 3-month modified Rankin Scale score and 3-month mortality.

Study Overview

• Status: Recruiting
• Conditions: Posterior Reversible Encephalopathy Syndrome
• Intervention / Treatment: Biological: Blood copeptin monitoring; Other: phone interview

Detailed Description

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity associating various neurological manifestations (e.g., encephalopathy, seizures) with a typical subcortical brain edema. While the pathophysiology of PRES remains elusive, the involvement of the arginine vasopressin (AVP) axis has recently been suggested by its stimulation in almost all etiologies of PRES as well as by its pathogenesis in the generation of brain edema that has been established in different preclinical models (e.g., traumatic brain injury, intracerebral hemorrhage) (Largeau et al., Mol Neurobiol 2019 - PMID: 30924075). Copeptin, a stable peptide derived from the same precursor as AVP and released in an equimolar ratio to AVP, is largely used in vivo to monitor AVP secretion. In a series of 225 critically ill patients free from PRES, median copeptin admission level was 50 pmol/L (Krychtiuk et al., PLOS ONE 2017- PMID: 28118414). By analogy to copeptin kinetics in patients with traumatic brain injury (Dong et al., J Trauma 2011 - PMID: 21502880), copeptin could attain peak level during the first week of PRES.

Blocking vasopressin receptors with vaptan appears to be a promising approach for PRES treatment. This study aims to investigate the relationship between copeptin and PRES in order to establish the optimal therapeutic time window for vaptan treatment against PRES.

XPRESSE is a multicenter observational prospective biomarker study in which critically ill patients in 4 French ICUs with MRI-based PRES diagnosis will have copeptin kinetics from a daily blood sample for 6 days and a 3-month follow-up.

Data collection using an eCRF will include demographic data, medical history and data related to PRES: onset modalities and date of symptoms control, radiological features of PRES, biological investigations, results of etiological investigations and therapeutic management (e.g., anticonvulsants, antihypertensive drugs, supportive treatments). Outcomes will include modified Rankin scale score and Glasgow Outcome Scale score at ICU discharge, 3-month modified Rankin Scale score and 3-month mortality.

• Study Type: Observational
• Enrollment (Estimated): 24

Contacts and Locations

• Study Contact: Name: Charlotte SALMON GANDONNIERE, MD, PhD; Phone Number: (+33)2 47 47 38 55; Email: charlotte.salmon.gandonniere@gmail.com

Study Locations

• France
  • Nantes, France, 44000
    • Recruiting
    • University Hospital
    • Contact: Jean REIGNIER, MD, PhD; Email: jean.reignier@chu-nantes.fr
    • Principal Investigator: Jean REIGNIER, MD, PhD
  • Orléans, France, 45000
    • Recruiting
    • Hospital
    • Contact: Grégoire MULLER, MD; Email: gregoire.muller@chr-orleans.fr
    • Principal Investigator: Grégoire MULLER, MD
  • Rennes, France, 35033
    • Recruiting
    • University Hospital
    • Contact: Flora DELAMAIRE, MD; Email: Flora.DELAMAIRE@chu-rennes.fr
    • Sub-Investigator: Benoit PAINVAIN, MD
    • Principal Investigator: Flora DELAMAIRE, MD
  • Tours, France, 37000
    • Recruiting
    • University Hospital
    • Contact: Charlotte SALMON GANDONNIERE, MD, PhD; Phone Number: (+33)2 47 47 38 55; Email: charlotte.salmon.gandonniere@gmail.com
    • Principal Investigator: Charlotte SALMON GANDONNIERE, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Critically ill adult patients in ICU with PRES

Description

Inclusion Criteria:

• Age >= 18 years ;
• Obtaining the non-opposition ;
• Patient hospitalized in ICU;

• PRES diagnosed within the last 48 hours (before admission or during ICU stay), based on the following clinico-radiological criteria :

  • Presentation with acute clinical symptoms ;
  • Presence of known risk factor for PRES;
  • Distributions of T2 weighted imaging (T2WI) or T2-fluid attenuated inversion recovery (T2-FLAIR) hyperintensities compatible with PRES imaging patterns ;
  • No other possible causes of these neuroimaging abnormalities found.

Exclusion Criteria:

• Patient under legal protection ;
• Patient under guardianship or curatorship
• Pregnant women.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group; Critically ill adult patients meeting all eligibility criteria with MRI-based PRES diagnosis within the last 48 hours	Biological: Blood copeptin monitoring; Blood copeptin monitoring during the first 6 days of ICU stay with PRES; Other: phone interview; Structured phone interview at 3 months to collect vital status and modified Rankin Scale score

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimation of time to maximum blood copeptin concentration (Tmax)	Tmax will be estimated from copeptin kinetics: 6 samples at about 24 hours interval during the first 6 days of ICU stay with PRES	Up to 120 hours post-baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimation of Tmax according to the etiology of PRES		Up to 120 hours post-baseline
Estimation of Tmax according to the type of MRI-based brain edema at diagnosis	Diffusion-weighted imaging (DWI) sequences and Apparent diffusion coefficient (ADC) maps will be used to discriminate a cytotoxic pattern of edema from a vasogenic edema	Up to 120 hours post-baseline
Estimation of Area Under the Curve from D0 to D5 (AUC D0-D5) of blood copeptin according to the etiology of PRES	AUC D0-D5 will be estimated from copeptin kinetics: 6 samples at about 24 hours interval during the first 6 days of ICU stay with PRES	Up to 120 hours post-baseline
Estimation of AUC D0-D5 of blood copeptin according to the type of MRI-based brain edema at diagnosis	DWI sequences and ADC maps will be used to discriminate a cytotoxic pattern of edema from a vasogenic edema	Up to 120 hours post-baseline
Estimation of time to reach a copeptin concentration ≤50 pmol/L according to the etiology of PRES		Up to 120 hours post-baseline
Estimation of time to reach a copeptin concentration ≤50 pmol/L according to the type of MRI-based brain edema at diagnosis	DWI sequences and ADC maps will be used to discriminate a cytotoxic pattern of edema from a vasogenic edema	Up to 120 hours post-baseline
Correlation analysis between AUC D0-D5 of blood copeptin and the extent of T2-FLAIR hyperintensities at diagnosis		Up to 120 hours post-baseline
Correlation analysis between AUC D0-D5 of blood copeptin and ADC values at diagnosis		Up to 120 hours post-baseline
Association analysis between AUC D0-D5 of blood copeptin and cerebral hemorrhagic lesions at diagnosis		Up to 120 hours post-baseline
Association analysis between AUC D0-D5 of blood copeptin and contrast enhancement in the brain at diagnosis		Up to 120 hours post-baseline
Correlation analysis between AUC D0-D5 of blood copeptin and AUC D0-D5 of mean arterial pressure		Up to 120 hours post-baseline
Correlation analysis between AUC D0-D5 of blood copeptin and AUC D0-D5 of serum creatinine		Up to 120 hours post-baseline
Association analysis between AUC D0-D5 of blood copeptin and Glasgow Outcome Scale score < 4 at ICU discharge	Glasgow Outcome Scale score: [1: Death, 2: Persistent vegetative state, 3: Severe disability, 4: Moderate disability, 5: Low disability]	0, 24, 48, 72, 96, 120 hours post-baseline and ICU discharge
Association analysis between AUC D0-D5 of blood copeptin and modified Rankin Scale score ≥ 4 at 3-month follow-up	Day-90 modified Rankin scale will be determined during a structured phone interview. Modified Rankin Scale score: [0: No symptoms at all, 1: No significant disability, 2: Slight disability, 3: Moderate disability, 4: Moderately severe disability, 5: Severe disability]	0, 24, 48, 72, 96, 120 hours post-baseline and 3 months
Association analysis between AUC D0-D5 of blood copeptin and mortality at 3-month follow-up		0, 24, 48, 72, 96, 120 hours post-baseline and 3 months

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Study Chair: Bérenger LARGEAU, PharmD, University Hospital, Tours; Principal Investigator: Charlotte SALMON GANDONNIERE, MD, PhD, University Hospital, Tours

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2022
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: June 14, 2021
• First Submitted That Met QC Criteria: July 2, 2021
• First Posted (Actual): July 6, 2021

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Intensive Care; Posterior Leukoencephalopathy Syndrome; Antidiuretic hormone
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Disease; Leukoencephalopathies; Hypertensive Encephalopathy; Intracranial Hypertension; Syndrome; Brain Diseases; Posterior Leukoencephalopathy Syndrome; Physiological Effects of Drugs; Natriuretic Agents; Hemostatics; Coagulants; Vasoconstrictor Agents; Antidiuretic Agents; Arginine Vasopressin
• Other Study ID Numbers: RIPH3-AOJCE20-BL-XPRESSE

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