Ignite Creation Date:
2024-05-06 @ 1:23 PM
Last Modification Date:
2024-10-26 @ 1:13 PM
Study NCT ID:
NCT04006106
Status:
COMPLETED
Last Update Posted:
2024-04-30
First Post:
2019-05-29
Brief Title:
Defining ENDOtypes in Perioperative Hypersensitivity by Extensive Cellular and Molecular PHENotyping ENDOPHEN
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Defining ENDOtypes in Perioperative Hypersensitivity by Extensive Cellular and Molecular PHENotyping and Assessment of Their Association to Severity
Status:
COMPLETED
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ENDOPHEN
Brief Summary:
Perioperative Acute Hypersensitivity PAH is a systemic reaction that occurs rapidly following injection of a drug during anesthesiaThe HSA-PA reaction must occur within a maximum of one hour after the induction of anesthesia or a new product by the anesthetist The main mechanism evoked is an immune response of immediate systemic hypersensitivity or anaphylaxis Anaphylactic reactions are classically described as IgE-dependent and triggered by the injection of allergen which by bridging specific IgE present on the surface of mast cells induces a massive release of histamine responsible for the observed symptoms The diagnosis of this mechanism IgE endotype requires the determination of associated circulating mediators histamine and mast cell tryptase as well as skin tests performed during an allergologic evaluation However our previous work on patients with PAH NASA study ClinicalTrialsgov NCT01637220 demonstrated that classical markers of IgE endotype are present in only 42 of patients This finding has three consequences
a diagnostic inaccuracy with deleterious consequences for the patient
the existence of undocumented endotypes explaining the observed clinical manifestations
a lack of formal identification of culprit drug with uncertainty about the eviction recommendations leading to consequences for the safety of the patient
The investigators hypothesize that symptoms associated with PAH are caused by several distinct endotypes involving different cellular effectors and molecular mediators These endotypes may be related to the immune system but independent of IgE or independent of the immune system
To assess these endotypes The investigators will be measuring the activation status of blood cells and a wide range of secreted mediators in blood drawn as soon as possible after PAH onset and at steady state during a subsequent allergology visit These data will be analyzed along with clinical data in multivariate analysis and clustering to define coherent profiles among patients
Definition of previously unexplored endotypes will allow to explain more PAH reactions and to design new diagnostic and therapeutic strategies
During the ENDOPHEN protocol the measurement of a large number of biological parameters will be correlated with the clinical phenotype in patients who have presented a PAH However the procedures of general anesthesia themselves lead to a certain number of physiological modifications likely to modify the parameters measured in the ENDOPHEN protocol This is why it was decided to carry out an ancillary study the PHENZERO study the objective of which is to measure the reference values of the parameters provided for in ENDOPHEN in an anesthetized population without any hypersensitivity phenotype zero phenotype
a diagnostic inaccuracy with deleterious consequences for the patient
the existence of undocumented endotypes explaining the observed clinical manifestations
a lack of formal identification of culprit drug with uncertainty about the eviction recommendations leading to consequences for the safety of the patient
The investigators hypothesize that symptoms associated with PAH are caused by several distinct endotypes involving different cellular effectors and molecular mediators These endotypes may be related to the immune system but independent of IgE or independent of the immune system
To assess these endotypes The investigators will be measuring the activation status of blood cells and a wide range of secreted mediators in blood drawn as soon as possible after PAH onset and at steady state during a subsequent allergology visit These data will be analyzed along with clinical data in multivariate analysis and clustering to define coherent profiles among patients
Definition of previously unexplored endotypes will allow to explain more PAH reactions and to design new diagnostic and therapeutic strategies
During the ENDOPHEN protocol the measurement of a large number of biological parameters will be correlated with the clinical phenotype in patients who have presented a PAH However the procedures of general anesthesia themselves lead to a certain number of physiological modifications likely to modify the parameters measured in the ENDOPHEN protocol This is why it was decided to carry out an ancillary study the PHENZERO study the objective of which is to measure the reference values of the parameters provided for in ENDOPHEN in an anesthetized population without any hypersensitivity phenotype zero phenotype
Detailed Description:
Background
Perioperative Acute Hypersensitivity PAH is a systemic reaction that occurs rapidly following injection of a drug during anesthesia Symptoms may include erythema angioedema bronchoconstriction vasodilation and increased capillary permeability leading to severe hypotension or even cardiac arrest The rate of occurrence is estimated between 16000 and 120000 anesthesia according to literature Despite adequate management mortality is estimated between 3 and 9 The main substances responsible for these reactions are the neuromuscular blocking agents NMBA and beta-lactams more rarely the gelatin-based filling solutions contrast agents antiseptics or other hypnotic or analgesic drugs The main mechanism is an immune response of immediate systemic hypersensitivity or anaphylaxis Anaphylactic reactions are classically described as IgE-dependent and triggered by the injection of allergen which by bridging specific IgE present on the surface of mast cells induces a massive release of histamine responsible for the observed symptoms The diagnosis of this mechanism IgE endotype requires the determination of associated circulating mediators histamine and mast cell tryptase as well as skin tests performed in an allergology consultation However our previous work on patients with NMBA-triggered PAH NASA study ClinicalTrialsgov NCT01637220 demonstrated that classical markers of IgE endotype are present in only 42 of patients This finding has three consequences
a diagnostic inaccuracy with deleterious consequences for the patient
the existence of undocumented endotypes explaining the observed clinical manifestations
a lack of formal identification of the culprit drug with uncertainty about the eviction recommendations leading to consequences for the safety of the patient
Hypothesis and aims The investigators hypothesize that symptoms associated with PAH are caused by several distinct endotypes involving different cellular effectors and molecular mediators These endotypes may be related to the immune system but independent of IgE or independent of the immune system
The main objective of this study is to characterize the different endotypes of PAH reactions by an exploratory clustering approach based on analysis of i activation state of blood cells and ii concentration of secreted mediators all measured during PAH onset
The secondary objectives are
to assess links between the different endotypes identified and the clinical and biological parameters of the PAH reaction in particular the severity and the responsible drug
Constitute a biobank serum plasma DNA to be able to continue the exploration of the different endotypes
Study design The investigators will include all patients 18 years old presenting during a general anesthesia symptoms compatible with a PAH severe enough to for the anesthetist to request biological exploration using the anaphylaxis kit tryptase histamine and specific IgE measurement The anaphylaxis kit will be modified to contain additional tubes allowing to measure blood cell counts blood cell activation flow cytometry proteic and lipidic mediators Clinical data about the reaction will be collected by the local investigator via an electronic form
Upon recovery patients will sign informed consent and will be planned for allergological evaluation 6-8 weeks after standard care During allergological evaluation skin test against all drugs received will be performed and blood will be drawn to measure tryptase and specific IgE as per standard care Additional tubes will allow to measure the same parameters as at inclusion and additionally to recover DNA and peripheral mononucleated blood cells
Outcomes and analyses The main goal is to define sets of biological parameters corresponding to distinct endotypes The data will be submitted to principal component analysis PCA to determine groups of patients with distinct profiles and which parameters are the more relevant for each profile Unsupervised hierarchical clustering will also be used to define groups of patients with distinct clinical and biological profiles
To assess the link between severity and clinicalbiological data logistic regression models will be used as well as severity-adjusted PCA
Perioperative Acute Hypersensitivity PAH is a systemic reaction that occurs rapidly following injection of a drug during anesthesia Symptoms may include erythema angioedema bronchoconstriction vasodilation and increased capillary permeability leading to severe hypotension or even cardiac arrest The rate of occurrence is estimated between 16000 and 120000 anesthesia according to literature Despite adequate management mortality is estimated between 3 and 9 The main substances responsible for these reactions are the neuromuscular blocking agents NMBA and beta-lactams more rarely the gelatin-based filling solutions contrast agents antiseptics or other hypnotic or analgesic drugs The main mechanism is an immune response of immediate systemic hypersensitivity or anaphylaxis Anaphylactic reactions are classically described as IgE-dependent and triggered by the injection of allergen which by bridging specific IgE present on the surface of mast cells induces a massive release of histamine responsible for the observed symptoms The diagnosis of this mechanism IgE endotype requires the determination of associated circulating mediators histamine and mast cell tryptase as well as skin tests performed in an allergology consultation However our previous work on patients with NMBA-triggered PAH NASA study ClinicalTrialsgov NCT01637220 demonstrated that classical markers of IgE endotype are present in only 42 of patients This finding has three consequences
a diagnostic inaccuracy with deleterious consequences for the patient
the existence of undocumented endotypes explaining the observed clinical manifestations
a lack of formal identification of the culprit drug with uncertainty about the eviction recommendations leading to consequences for the safety of the patient
Hypothesis and aims The investigators hypothesize that symptoms associated with PAH are caused by several distinct endotypes involving different cellular effectors and molecular mediators These endotypes may be related to the immune system but independent of IgE or independent of the immune system
The main objective of this study is to characterize the different endotypes of PAH reactions by an exploratory clustering approach based on analysis of i activation state of blood cells and ii concentration of secreted mediators all measured during PAH onset
The secondary objectives are
to assess links between the different endotypes identified and the clinical and biological parameters of the PAH reaction in particular the severity and the responsible drug
Constitute a biobank serum plasma DNA to be able to continue the exploration of the different endotypes
Study design The investigators will include all patients 18 years old presenting during a general anesthesia symptoms compatible with a PAH severe enough to for the anesthetist to request biological exploration using the anaphylaxis kit tryptase histamine and specific IgE measurement The anaphylaxis kit will be modified to contain additional tubes allowing to measure blood cell counts blood cell activation flow cytometry proteic and lipidic mediators Clinical data about the reaction will be collected by the local investigator via an electronic form
Upon recovery patients will sign informed consent and will be planned for allergological evaluation 6-8 weeks after standard care During allergological evaluation skin test against all drugs received will be performed and blood will be drawn to measure tryptase and specific IgE as per standard care Additional tubes will allow to measure the same parameters as at inclusion and additionally to recover DNA and peripheral mononucleated blood cells
Outcomes and analyses The main goal is to define sets of biological parameters corresponding to distinct endotypes The data will be submitted to principal component analysis PCA to determine groups of patients with distinct profiles and which parameters are the more relevant for each profile Unsupervised hierarchical clustering will also be used to define groups of patients with distinct clinical and biological profiles
To assess the link between severity and clinicalbiological data logistic regression models will be used as well as severity-adjusted PCA
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None