An interventional study of IgG group and IgE group in Hypersensitivity, Immediate, Peri-operative Injury and Antibiotic Allergy, sponsored by Assistance Publique - Hôpitaux de Paris. Recruiting at 1 site in France. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-09-19.
Sponsored by Assistance Publique - Hôpitaux de Paris · Not applicable, Interventional, and Basic science
Acute per-anesthetic hypersensitivity reaction (HSA-PA) is a rapidly occurring systemic reaction following injection of a drug during anesthesia (mortality between 3 and 9%). The substances responsible for these reactions in France are curare in 60% of cases, followed by antibiotics. The main mechanism mentioned is an immediate systemic hypersensitivity immune reaction mediated by IgE antibodies (anaphylaxis). NeuroMuscular Blocking Agents (NMBA; curare) relax skeletal muscles to facilitate surgeries and permit intubation, but lead to adverse reactions: (a) severe hypersensitivity reactions (anaphylaxis) thought to rely on pre-existing anti-NMBA antibodies; (b) complications due to postoperative residual curarization. Identification of patients at risk remains suboptimal due to the lack of adequate tools to detect anti-NMBA antibodies. A capturing agent exists for only one out of the four most used NMBAs, allowing reversal of profound curarization. Case reports suggested that it might also ameliorate an ongoing anaphylaxis due to that NMBA.
Based on strong preliminary results, our study proposes to characterize anti-drugs antibody repertoires in patients with various NMBA or antibiotics-anaphylaxis, describe activation pathways leading to anaphylaxis, develop and validate diagnostic and therapeutic molecules to ameliorate patient screening, NMBA-anaphylaxis and reverse profound neuromuscular block.
Acute per-anesthetic hypersensitivity reaction (HSA-PA) is a rapidly occurring systemic reaction following injection of a drug during anesthesia (mortality between 3 and 9%). The substances responsible for these reactions in France are curare in 60% of cases, followed by antibiotics. The main mechanism mentioned is an immediate systemic hypersensitivity immune reaction mediated by IgE antibodies (anaphylaxis).
NeuroMuscular Blocking Agents (NMBA; curare) used in the clinic (e.g., atracurium, suxamethonium, rocuronium, vecuronium) belong to the curare family and block the nicotinic acetylcholine receptor to cause muscle relaxation. They share the presence of quaternary ammonium groups that are required for binding the acetylcholine receptor, and thus for their biological activity. Even though NMBA are relatively safe molecules, two main types of adverse reactions have been reported.
The most striking are immediate and severe anti-drug reactions at NMBA infusion with 1/10,000 patients suffering from severe hypersensitivity reactions, i.e. anaphylaxis. Anaphylaxis is classically considered to rely on IgE antibodies against the culprit compound, and to involve massive histamine liberation by mast cells and basophils, following antigen-induced aggregation of IgE receptor (FcεRI)-bound specific IgE antibodies1. The clinical diagnosis of anaphylaxis to NMBA is based on this IgE paradigm. NMBA quaternary ammonium cations are considered their major allergenic epitopes2, even if patients are rarely hypersensitive to several NMBA, even closely related NMBA like rocuronium and vecuronium that derive from each other, suggesting that antibodies may bind NMBA-specific structures other than quaternary ammoniums. Antibodies may even interact with NMBA as a "whole" epitope due to NMBA very reduced size; NMBA indeed vary from 300-1,000 Da. Intriguingly, 10-20% of patients who experience NMBA-induced anaphylaxis do not present with any biological signs of IgE-dependent immune activation, suggestive of other potential mechanisms. 4 An IgG antibody pathway has recently been described in NMBA-induced human anaphylaxis, leading to Platelet-Activating Factor release, neutrophil and platelet activation, which may aggravate anaphylaxis in combination with the IgE-pathway or underlie anaphylaxis in the absence of specific IgE.
The other most common adverse reaction is not allergic in nature, and is due to prolonged presence of NMBA following surgery, i.e. "residual curarization". This very frequent complication (up to 83% of the patients) leads to adverse postoperative pulmonary events, pharyngeal dysfunction, urgent tracheal reintubation and prolonged stay in post-anesthesia care units that lead to a high economic burden13. The first option for pharmacological neuromuscular blockade reversal, prostigmine (used for atracurium reversal), is restricted to situations where half of the spontaneous reversal is effective. The second one is a synthetic cyclodextrin, sugammadex, that captures rocuronium or vecuronium in vivo within minutes following injection. Instant blockade reversal might be necessary, as in difficult intubation scenarios, explaining that it has been considered economically advantageous to administer sugammadex despite a cost of $100/dose, leading to a $400-$3,000 economy per patient.
Based on strong preliminary results, our study proposes to characterize anti-drugs antibody repertoires in patients with various NMBA or antibiotics-anaphylaxis, describe activation pathways leading to anaphylaxis, develop and validate diagnostic and therapeutic molecules to ameliorate patient screening, NMBA-anaphylaxis and reverse profound neuromuscular block.
82 studies on the registry are indexed under Hypersensitivity, Immediate; 7 are open to participants now.
This study's planned enrollment of 40 is below the median of 70 across 66 interventional studies indexed under Hypersensitivity, Immediate.
Browse Hypersensitivity, Immediate studies →Assistance Publique - Hôpitaux de Paris is the lead sponsor of 3,592 studies on the registry; 1,033 are open to participants now.
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Common to both groups:
For IgE group:
For the IgG group:
Exclusion Criteria:
Common to both groups:
For IgE group:
Prerequisites for carrying out the sternal sample in order to carry out a myelogram (IgE group):
For the IgG group
Prerequisites for performing the blood sample (IgG group):
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patient in the IgG group will benefit from a blood sampling of 5 ml (for realization of a basophil activation test) and a blood sampling of 250 ml
Diagnostic Test: IgG group
Patient in the IgE will benefit from a blood sampling of 5 ml (for realization of a basophil activation test) and a bone marrow sampling (approx 2 ml)
Diagnostic Test: IgE group
Patient in the IgG + IgE will benefit from a blood sampling of 5 ml (for realization of a basophil activation test), a blood sampling of 250 ml and a bone marrow sampling (approx 2 ml)
Diagnostic Test: IgG group + IgE group
Will be performed : * a blood sampling of 5 ml (for realization of a basophil activation test) * a blood sampling of 250 ml
Will be performed : * a blood sampling of 5 ml (for realization of a basophil activation test) * a bone marrow sampling
* a blood sampling of 5 ml (for realization of a basophil activation test) * a blood sampling of 250 ml * a bone marrow sampling
Obtain sequences of gene producers (VH and VL pairs) coding for the variable part of anti-drug antibodies, thanks to the isolation of B lymphocytes of antibodies directed against the responsible molecule, from blood cells or bone marrow
Time frame: up to 10 years
Production of recombinant antibodies based on obtained sequences
Purification system (AKTA 25L, Cytiva)
Time frame: up to 10 years
Evaluate antibodies properties, such as specificity
ELISA
Time frame: up to 10 years
Evaluate antibodies properties, such as avidity
Interferometry (Octet, ForteBio)
Time frame: up to 10 years
Ability of antibodies expressed as N297A mutated human IgG1 to reduce or block target curare-induced neuromuscular blockade without an immune response triggered by the antibody drug
Measure of muscle strength of mice
Time frame: up to 10 years
Ability of antibodies expressed as N297A mutated human IgG1 to reduce or block target curare-induced neuromuscular blockade without an immune response triggered by the antibody drug
Measure of motricity of mice
Time frame: up to 10 years
Ability of antibodies expressed as N297A mutated human IgG1 to reduce or block target curare-induced neuromuscular blockade without an immune response triggered by the antibody drug
Measure the survival rate of mice
Time frame: up to 10 years
Ability of antibodies expressed as N297A mutated human IgG1 to reduce or block target curare-induced neuromuscular blockade without an immune response triggered by the antibody drug
Evaluate the absence of occurrence of anaphylactic shock
Time frame: up to 10 years
Core temperature loss greater than 3°C within 60 minutes after target drug injection only in mice pre-injected with anti-drug IgE or IgG
Rectal probe thermometer for mice
Time frame: up to 10 years
Plan to share: No
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Started Apr 2023 (actual). Primary completion is estimated for Apr 2033, 120 months after the start.
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