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Repertoire and Properties of Anti-drug Antibodies Involved in Immediate Hypersensitivity in the Operating Room (MEDIREP)

Primary Purpose

Hypersensitivity, Immediate, Peri-operative Injury, Antibiotic Allergy

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
IgG group
IgE group
IgG group + IgE group
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Hypersensitivity, Immediate focused on measuring Hypersensitivity, IgE, IgG, repertoire, NMBA, anaphylaxis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Common to both groups:

  • Age ≥ 18 years old and ≤ 70 years old
  • Patient having presented an allergic reaction in the operating room in the last 10 years, regardless of the grade of severity, the causative agent or the type of anesthesia
  • Patient having benefited from an allergy-anaesthesia consultation in the investigator center

For IgE group:

- presence of at least one positive skin test to one of the suspected agent (curare and/or antibiotic) during the allergist consultation

For the IgG group:

- presence of circulating IgG-type antibodies directed against one of the suspected agents (curare, antibiotic, antiseptic), identified in the routine biological tests carried out at the time of the shock and / or the consultation of allergology.

Exclusion Criteria:

Common to both groups:

  • Absence of written informed consent
  • Protected person: under guardianship or curatorship
  • Patient without social security
  • Pregnancy of breast feeding
  • Ongoing immunosuppressive or chemotherapy
  • Acute heart failure
  • Patient included in another interventional research with an exclusion period

For IgE group:

  • Taking oral or injectable anticoagulants
  • Taking a double antiplatelet aggregation
  • Previous sternotomy
  • Previous thoracic radiation therapy
  • Known allergy to local anesthesic or ioda
  • Previous major sternal cutaneous lesions

Prerequisites for carrying out the sternal sample in order to carry out a myelogram (IgE group):

  • Leukocytes > 4 giga/L in the 2 months preceding inclusion
  • Platelets > 100,000 / mm3 in the 2 months preceding inclusion

For the IgG group

  • Orthostatic hypotension
  • Realization of a blood donation in the 6 to 8 weeks preceding inclusion

Prerequisites for carrying out the sternal sample in order to carry out a myelogram (IgE group):

  • Leukocytes > 4 giga/L in the 2 months preceding inclusion
  • Platelets > 100,000 / mm3 in the 2 months preceding inclusion

Prerequisites for performing the blood sample (IgG group):

- Hemoglobin > 12.5 g/dL for women and > 13 g/dL for men in the 2 months preceding inclusion

Sites / Locations

  • Hôpital Bichat claude BernardRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Other

Other

Arm Label

IgG group

IgE group

IgG group + IgE group

Arm Description

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

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)

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)

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Production of recombinant antibodies based on obtained sequences
Purification system (AKTA 25L, Cytiva)
Evaluate antibodies properties, such as specificity
ELISA
Evaluate antibodies properties, such as avidity
Interferometry (Octet, ForteBio)
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
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
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
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
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

Full Information

First Posted
May 20, 2022
Last Updated
October 23, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Institut Pasteur
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1. Study Identification

Unique Protocol Identification Number
NCT05420935
Brief Title
Repertoire and Properties of Anti-drug Antibodies Involved in Immediate Hypersensitivity in the Operating Room
Acronym
MEDIREP
Official Title
Repertoire and Properties of Anti-drug Antibodies Involved in Immediate Hypersensitivity in the Operating Room
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 12, 2023 (Actual)
Primary Completion Date
April 12, 2033 (Anticipated)
Study Completion Date
December 15, 2033 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Institut Pasteur

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypersensitivity, Immediate, Peri-operative Injury, Antibiotic Allergy, Antibody Hypersensitivity
Keywords
Hypersensitivity, IgE, IgG, repertoire, NMBA, anaphylaxis

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
IgG group
Arm Type
Other
Arm Description
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
Arm Title
IgE group
Arm Type
Other
Arm Description
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)
Arm Title
IgG group + IgE group
Arm Type
Other
Arm Description
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)
Intervention Type
Diagnostic Test
Intervention Name(s)
IgG group
Intervention Description
Will be performed : a blood sampling of 5 ml (for realization of a basophil activation test) a blood sampling of 250 ml
Intervention Type
Diagnostic Test
Intervention Name(s)
IgE group
Intervention Description
Will be performed : a blood sampling of 5 ml (for realization of a basophil activation test) a bone marrow sampling
Intervention Type
Diagnostic Test
Intervention Name(s)
IgG group + IgE group
Intervention Description
a blood sampling of 5 ml (for realization of a basophil activation test) a blood sampling of 250 ml a bone marrow sampling
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Production of recombinant antibodies based on obtained sequences
Description
Purification system (AKTA 25L, Cytiva)
Time Frame
up to 10 years
Title
Evaluate antibodies properties, such as specificity
Description
ELISA
Time Frame
up to 10 years
Title
Evaluate antibodies properties, such as avidity
Description
Interferometry (Octet, ForteBio)
Time Frame
up to 10 years
Title
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
Description
Measure of muscle strength of mice
Time Frame
up to 10 years
Title
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
Description
Measure of motricity of mice
Time Frame
up to 10 years
Title
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
Description
Measure the survival rate of mice
Time Frame
up to 10 years
Title
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
Description
Evaluate the absence of occurrence of anaphylactic shock
Time Frame
up to 10 years
Title
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
Description
Rectal probe thermometer for mice
Time Frame
up to 10 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Common to both groups: Age ≥ 18 years old and ≤ 70 years old Patient having presented an allergic reaction in the operating room in the last 10 years, regardless of the grade of severity, the causative agent or the type of anesthesia Patient having benefited from an allergy-anaesthesia consultation in the investigator center For IgE group: - presence of at least one positive skin test to one of the suspected agent (curare and/or antibiotic) during the allergist consultation For the IgG group: - presence of circulating IgG-type antibodies directed against one of the suspected agents (curare, antibiotic, antiseptic), identified in the routine biological tests carried out at the time of the shock and / or the consultation of allergology. Exclusion Criteria: Common to both groups: Absence of written informed consent Protected person: under guardianship or curatorship Patient without social security Pregnancy of breast feeding Ongoing immunosuppressive or chemotherapy Acute heart failure Patient included in another interventional research with an exclusion period For IgE group: Taking oral or injectable anticoagulants Taking a double antiplatelet aggregation Previous sternotomy Previous thoracic radiation therapy Known allergy to local anesthesic or ioda Previous major sternal cutaneous lesions Prerequisites for carrying out the sternal sample in order to carry out a myelogram (IgE group): Leukocytes > 4 giga/L in the 2 months preceding inclusion Platelets > 100,000 / mm3 in the 2 months preceding inclusion For the IgG group Orthostatic hypotension Realization of a blood donation in the 6 to 8 weeks preceding inclusion Prerequisites for performing the blood sample (IgG group): - Hemoglobin > 12.5 g/dL for women and > 13 g/dL for men in the 2 months preceding inclusion
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Aurelie Gouel, MD, PhD
Phone
00-33-1-40-25-83-55
Email
aurelie.gouel@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Pierre Bruhns, PhD
Phone
00-33-1-45-68-86-29
Email
bruhns@pasteur.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aurelie Gouel, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Bichat claude Bernard
City
Paris
ZIP/Postal Code
75018
Country
France
Individual Site Status
Recruiting

12. IPD Sharing Statement

Learn more about this trial

Repertoire and Properties of Anti-drug Antibodies Involved in Immediate Hypersensitivity in the Operating Room

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